Anthelmintic depsipeptide compounds

ABSTRACT

The present invention provides cyclic depsipeptide compounds of formula (I) and compositions comprising the compounds that are effective against parasites that harm animals, including humans. The compounds and compositions may be used for combating parasites in or on animals including mammals and birds. The invention also provides for an improved method for eradicating, controlling and preventing parasite infestation in animals, including birds and mammals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/272,040 filed on Dec. 28, 2015, which is herein incorporated byreference.

FIELD OF THE INVENTION

The present invention is directed to new anthelmintic depsipeptidescompounds with improved activity against endoparasites andectoparasites. The invention is also directed to compositions comprisingthe compounds and methods and uses of the compounds for eradicating,controlling, and preventing a parasite infestation and/or infection inanimals. The compounds of the invention may be administered to animals,particularly mammals, fish and birds, to prevent or treat parasiticinfections and/or infestations.

BACKGROUND OF THE INVENTION

Animals, including mammals (including humans), fish and birds, are oftensusceptible to parasite infestations and infections. These parasites maybe ectoparasites, such as fleas and ticks. Animals also suffer fromendoparasitic infections including, for example, helminthiasis which ismost frequently caused by a group of parasitic worms described asnematodes or roundworms. These parasites cause severe economic losses inpigs, sheep, horses, and cattle as well as affecting domestic animalsand poultry. Other parasites which occur in the gastrointestinal tractof animals and humans include Ancylostoma, Necator, Ascaris,Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris,Enterobius and parasites which are found in the blood or other tissuesand organs such as filarial worms and the extra intestinal stages ofStrongyloides, Toxocara and Trichinella.

One type of endoparasite which seriously harms mammals is Dirofilariaimmitis, also known as Heartworm. Other filarial endoparasites includeDirofilaria repens and Dirofilaria honkongensis, which can also infecthumans. The most common hosts are dogs and cats but other mammals suchas ferrets and raccoons may also be infected. Heartworms go throughoutseveral life stages before they become adults infecting the pulmonaryartery of the host mammal. The worms require the mosquito as anintermediate host to complete their life cycle. The period between theinitial infection when the dog is bitten by a mosquito and thematuration of the worms into adults living in the heart and pulmonaryarteries is six to seven months in dogs and is known as the “prepatentperiod”. L3 larvae migrate during blood feeding of the mosquito to thetip of the mosquito's mouth parts (labium), leave the mosquito and aredeposited on the skin of the dog where they then migrate through thebite wound into the host. Most L3 larvae molt to fourth-stage larvae(L4s) in canine subcutaneous tissues within 1-3 days after infection.Then, they migrate to the muscles of the chest and abdomen, and 45 to 60days after infection, molt to the fifth stage (L5, immature adult).Between 75 and 120 days after infection, these immature heartworms thenenter the bloodstream and are carried through the heart to reside in thepulmonary artery. Around seven months after infection, Dirofilariaimmitis adults reach maturity and sexually reproduce in the pulmonaryarteries and right ventricle. Adult males are around 15 cm in length,and females are around 25 cm in length and their normal life span asadults is calculated to be about 5 years.

Heartworm infection is a severe and life-threatening disease. Canineheartworm infection is preventable and prophylaxis treatment is apriority in heartworm endemic areas. Treatment of mature heartworminfection with an adulticide (e.g. melarsomine dihydrochloride) iscostly and can cause serious adverse side effects, thus prevention bymonthly administration of drugs that interrupt larvae development iswidely used. The goal of marketed heartworm preventive therapies in dogsis to prevent the development of the parasite to adult heartworms byinterrupting the Dirofilaria immitis life cycle post-infection.

The macrocyclic lactones (MLs, e.g. ivermectin, milbemycin oxime,moxidectin, and selamectin) are the most commonly used chemoprophylaxisagents and are administered at monthly or six-month intervals. Thesedrugs have been effective against Dirofilaria immitis infectivethird-stage larvae (L3) deposited by the mosquito as well as maturingfourth-stage larvae (L4). When administered monthly, MLs kill L3 and L4larvae acquired within the previous 30 days, and thus prevent diseasecaused by adult worms. MLs can also be used monthly in infected dogs tosuppress reproduction in adult worms and remove microfilariae, therebyreducing transmission and gradually causing the attrition of adult worms(Vet Parasitol 2005 Oct. 24 133(2-3) 197-206).

In recent years, an increased number of lack of efficacy (LOE) caseshave been reported, in which dogs develop mature heartworm infectionsdespite receiving monthly prophylactic doses of macrocyclic lactonesdrugs. For example, Atkins et al, (Veterinary Parasitology 206 (2014)106-113) recently reported that an increasing number of cases of dogsthat tested heartworm antigen positive while receiving heartwormpreventive medication which suggests that some populations ofDirofilaria immitis have developed selectional resistance to heartwormpreventives (American Heartworm Society, 2010. Heartworm PreventiveResistance. Is it Possible, vol. 37. Bulletin of the American HeartwormSociety, pp. 5.). Thus, there is an ongoing need to develop newanthelmintic agents with improved activity against Dirofilaria immitisand other endoparasites.

Various parasiticides exist in the art for treating endoparasitesinfections in animals. In addition to the macrocyclic lactones, cyclicdepsipeptides with antiparasitic activity are known. PF1022A is a24-membered cyclic depsipeptide isolated from the fungus Myceliasterilia by Sasaki et al. (see J. Antibiotics 45: 692-697 (1992)) hasbeen found to exhibit broad anthelmintic activity against a variety ofendoparasites in vivo with low toxicity. These compounds are described,for example, in U.S. Pat. Nos. 5,514,773; 5,747,448; 5,646,244;5,874,530; among others, which are incorporated herein by reference.Emodepside is a semi synthetic analog of PF1022A containing a morpholinegroup at the para position of the phenyl lactate groups. Emodepside is apotent anthelmintic used in combination with praziquantel in the productProfender® for the treatment of parasitic worms in cats and dogs.Recently, Scherkenbeck et al., described the synthesis of analogs ofPF1022A in which the phenyl group in the phenyl lactate moieties of themolecule were substituted with heteroaromatic groups (Letters in OrganicChemistry, 2016, 13, 441-445). However, the antiparasitic activity ofPF1022A and emodepside is not satisfactory for the treatment of certainparasites, especially for the control of Dirofilaria immitis in mammalsto prevent the establishment of Heartworm disease. Thus, there is a needin the art for more effective antiparasitic agents for treatment andprotection of animals, e.g. mammals, fish and birds against parasites,in particular internal parasites including nematodes and filarial wormssuch as Heartworm.

It is expressly noted that citation or identification of any document inthis application is not an admission that such document is available asprior art to the present invention. Any foregoing applications, and alldocuments cited therein or during their prosecution (“application citeddocuments”) and all documents cited or referenced in the applicationcited documents, and all documents cited or referenced herein (“hereincited documents”), and all documents cited or referenced in herein citeddocuments, together with any manufacturer's instructions, descriptions,product specifications, and product sheets for any products mentionedherein or in any document incorporated by reference herein, are herebyincorporated herein by reference, and may be employed in the practice ofthe invention.

SUMMARY OF THE INVENTION

The invention provides novel and inventive cyclic depsipeptide compoundswith superior anthelmintic activity and possibly also superior activityagainst ectoparasites in certain embodiments. In addition the inventionprovides compositions comprising the novel depsipeptide compounds andmethods for the treatment and prevention of parasitic infection andpossibly infestation of animals using the compounds. In certainembodiments, the cyclic depsipeptide compounds of formula (I) may beused to treat parasitic infections in humans.

In one embodiment, the present invention provides cyclic depsipeptidecompounds of formula (I) shown below:

or a pharmaceutically or veterinarily acceptable salt thereof, whereinthe meanings of variables R¹, R^(1′), R², R^(2′), R³, R^(3′), R⁴,R^(4′), Cy¹, Cy², R^(a), R^(b), R′, R″, R′″ and R″″ are as describedbelow. The invention also provides veterinary compositions comprisingthe inventive compounds, or salts thereof, in combination with apharmaceutically acceptable carrier or diluent.

The compounds of the invention are intended to encompass racemicmixtures, specific stereoisomers and tautomeric forms of the compound.Another aspect of the invention is a salt form of the compound of theinvention.

The inventive compounds and compositions comprising the compounds arehighly effective for the treatment and prophylaxis of internal parasitesin animals including mammals, fish and birds, and in particular, humans,cats, dogs, horses, chickens, pigs, sheep and cattle with the aim ofridding these hosts of all the endoparasites commonly encountered bymammals, fish and birds.

In one embodiment, the compounds and compositions of the invention arehighly effective against endoparasites, such as filariae (e.g.Heartworm), hookworms, whipworms and roundworms of the digestive tractof animals (including humans). In certain embodiments, the compounds andcompositions of the invention are effective against Dirofilaria immitis(Heartworm) isolates that are less sensitive to treatment withmacrocyclic lactones. In another embodiment, the novel and inventivedepsipeptides of the invention are effective for treating and preventinginfections of animals with nematodes that are less sensitive totreatment with commercially available or known macrocyclic lactoneactive agents.

In certain embodiments, the invention provides compositions comprising acombination of a novel depsipeptide of the invention in combination withat least a second active agent, which broadens the scope of protectionafforded to animals against endoparasites and possibly alsoectoparasites.

The present invention is also directed to methods for the treatment andprevention of a parasitic infection or infestation in an animalcomprising administering at least one of the compounds of formula (I) ofthe invention to the animal. Also included in the present invention areuses of the compounds for the treatment and/or prevention of a parasiticinfections and infestations in animals and the use of the compounds inthe preparation of a medicament for the treatment and/or prevention of aparasitic infection in an animal.

It is an object of the invention to not encompass within the inventionany previously known product, process of making the product, or methodof using the product such that the Applicants reserve the right to thisinvention and hereby disclose a disclaimer of any previously knownproduct, process, or method.

It is noted that in this disclosure and particularly in the claimsand/or paragraphs, terms such as “comprises”, “comprised”, “comprising”and the like can have the meaning attributed to it in U.S. Patent law;e.g., they can mean “includes”, “included”, “including”, and the like;and that terms such as “consisting essentially of” and “consistsessentially of” have the meaning ascribed to them in U.S. Patent law;e.g., they allow for elements not explicitly recited, but excludeelements that are found in the prior art or that affect a basic or novelcharacteristic of the invention.

These and other embodiments are disclosed or are obvious from, andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION

The present invention provides novel and inventive cyclic depsipeptidecompounds of formula (I) having parasiticidal activity againstendoparasites and also against ectoparasites in certain embodiments, orveterinarily salts thereof, and compositions comprising the compounds orsalts for the treatment or prevention of parasitic infestations and/orinfection in an animal Also provided are methods for the treatment orprevention of parasitic infestations and/or infection in animals,comprising administering an effective amount of the depsipeptidecompound of the invention, or a salt thereof, to the animal.

The novel and inventive cyclic depsipeptide of formula (I) describedherein and their pharmaceutically acceptable salts are particularlyeffective for controlling endoparasites. Endoparasites include, but arenot limited to, nematodes (such as roundworms, hookworms, and whipworms)and filarial worms such as Dirofilaria immitis (Heartworm). In certainembodiments, the novel cyclic depsipeptides of the invention have beenfound to have significantly higher efficacy against endoparasitescompared with known cyclic depsipeptides including PF1022A andemodepside. In other embodiments, the novel cyclic depsipeptides of theinvention have also been surprisingly found to have an improved safetyprofile (lower toxicity to mammals) compared to cyclic depsipeptides ofthe prior art such as PF1022A and emodepside. Furthermore, it has beendiscovered that the novel cyclic depsipeptides of the invention aresignificantly more resistant to metabolic modification in the body ofanimals so that they maintain at a higher concentration in the hostanimal's body and a higher level of activity against internal parasitesfor a longer duration of time.

In one embodiment, the cyclic depsipeptides of the invention have beenfound to be highly effective against filarial worms such as Dirofilariaimmitis (microfilarial and larval stages), including isolates of theparasite that are less sensitive to treatment with macrocyclic lactones.In other embodiments, the compounds of the invention are effectiveagainst endoparasites that are not effectively controlled by the knowncyclic depsipeptides such as PF1022A and emodepside.

In another embodiment, the cyclic depsipeptides of the invention havebeen found to have activity against ectoparasites such as fleas andticks. Thus, in certain embodiments the cyclic depsipeptides may haveendectocidal activity against both internal and external parasites.

The invention includes at least the following features:

(a) In one embodiment, the invention provides novel cyclic depsipeptidecompounds of formula (I), or pharmaceutically or veterinarily acceptablesalts thereof, which are active endoparasites and in some cases alsoactive against ectoparasites;

(b) veterinary and pharmaceutical compositions comprising aparasiticidally effective amount of the cyclic depsipeptide compounds offormula (I), or a pharmaceutically or veterinarily salts thereof, incombination with a pharmaceutically or veterinarily acceptable carrieror diluent;

(c) veterinary and pharmaceutical compositions comprising aparasiticidally effective amount of the cyclic depsipeptide compounds ofthe invention, or pharmaceutically or veterinarily acceptable saltsthereof, in combination with one more other active agents and apharmaceutically or veterinarily acceptable carrier or diluent;

(d) methods for treating a parasitic infestation/infection in or on ananimal are provided comprising administering a parasiticidally effectiveamount of a cyclic depsipeptide compound of formula (I), or apharmaceutically or veterinarily acceptable salts thereof, to the animalin need thereof;

(e) methods for the prevention of a parasitic infestation/infection ofan animal, which comprise administering a parasiticidally effectiveamount of a cyclic depsipeptide compound of formula (I), orpharmaceutically or veterinarily acceptable salts thereof, with one ormore additional active agents, to the animal in need thereof;

(f) use of the cyclic depsipeptide compounds of formula (I), orpharmaceutically or veterinarily acceptable salts thereof, for thetreatment or prevention of a parasitic infection and possibly also aparasitic infestation in an animal;

(g) use of the cyclic depsipeptide compounds of formula (I), orpharmaceutically or veterinarily acceptable salts thereof, in themanufacture of a medicament for the treatment or prevention of aparasitic infection in an animal; and

(h) processes for the preparation of the compounds of formula (I).

Definitions

Terms used herein will have their customary meanings in the art unlessspecified. The organic moieties mentioned in the definitions of thevariables of the cyclic depsipeptide formula (I) are like the termhalogen—i.e., collective terms for individual listings of the individualgroup members—fluoro, chloro, bromo and iodo in with respect to halogen.The prefix C_(n)-C_(m) indicates in each case the possible number ofcarbon atoms in the group.

The term “alkyl” refers to saturated straight, branched, primary,secondary or tertiary hydrocarbons, including those having 1 to 12atoms. In some embodiments, alkyl groups will include C₁-C₁₀, C₁-C₈,C₁-C₆, C₁-C₄ or C₁-C₃ alkyl groups. Examples of C₁-C₁₀ alkyl include,but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl,2-ethylhexyl, nonyl and decyl and their isomers. C₁-C₄-alkyl means forexample methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl.

Preferably, unless otherwise indicated, when the “alkyl” group is asubstituent on another substituent, the alkyl group is unsubstituted.Moreover, preferably unless otherwise indicated, “alkyl” in the contextof the alkyl component of: alkylamino, di(alkyl)amino, alkoxy,alkoxyalkoxy, alkyl ester, haloalkoxy, alkylthio, thioalkyl,alkylthioalkyl, haloalkylthio, heteroalkyl, hydroxyalkyl, alkoxyalkyl,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,trialkylsilyl, etc., means alkyl as defined above, wherein the alkylcomponent is not further substituted.

Carbocyclic groups are cyclic groups composed exclusively of carbon. Thecarbocyclic groups include both aromatic rings such as phenyl andnon-aromatic rings such as cyclohexyl and include those with 3 to 14carbon atoms having single or multiple fused rings.

Cyclic alkyl groups, which are encompassed by alkyls, may be referred toas “cycloalkyl” and include those with 3 to 10 carbon atoms havingsingle or multiple fused rings. Non-limiting examples of cycloalkylgroups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, unlessotherwise indicated, when the “cycloalkyl” group is a substituent onanother substituent, the cycloalkyl group is unsubstituted.

The alkyl and cycloalkyl groups described herein can be unsubstituted orsubstituted with one or more moieties selected from the group consistingof alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino,alkyl- or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano,azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl,sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl,phosphine, thioester, thioether, acid halide, anhydride, oxime,hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, or anyother viable functional group that does not inhibit the biologicalactivity of the compounds of the invention, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Third Edition, 1999, hereby incorporatedby reference.

The term “alkenyl” refers to both straight and branched carbon chainswhich have at least one carbon-carbon double bond. Preferably, unlessotherwise indicated, when the “alkenyl” group is a substituent onanother substituent, the alkyl group is unsubstituted. In someembodiments, alkenyl groups may include C₂-C₁₂ alkenyl groups. In otherembodiments, alkenyl includes C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkenylgroups. In one embodiment of alkenyl, the number of double bonds is 1-3;in another embodiment of alkenyl, the number of double bonds is one.Other ranges of carbon-carbon double bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. “C₂-C₁₀-alkenyl” groups may include more than one double bondin the chain. Examples include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

“Cycloalkenyl” refers to monovalent cyclic alkenyl groups of from 4 to10 carbon atoms, preferably 5 to 8 carbon atoms, having single ormultiple fused rings which fused rings may or may not be cycloalkenylprovided that the point of attachment is to a cycloalkenyl ring atom.Examples of cycloalkenyl groups include, by way of example,cyclopenten-4-yl, cyclooctene-5-yl and the like. Alkenyl andcycloalkenyl groups may be unsubstituted or substituted with one or moresubstituents as described for alkyl above.

“Alkynyl” refers to both straight and branched carbon chains which haveat least one carbon-carbon triple bond. Preferably, unless otherwiseindicated, when the “alkynyl” group is a substituent on anothersubstituent, the alkynyl group is unsubstituted. In one embodiment ofalkynyl, the number of triple bonds is 1-3; in another embodiment ofalkynyl, the number of triple bonds is one. In some embodiments, alkynylgroups include from 2 to 12 carbon atoms. In other embodiments, alkynylgroups may include C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkynyl groups. Otherranges of carbon-carbon triple bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. For example, the term “C₂-C₁₀-alkynyl” as used herein refersto a straight-chain or branched unsaturated hydrocarbon group having 2to 10 carbon atoms and containing at least one triple bond, such asethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl,n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl,n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl,n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl,3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl,n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl,n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1yl,n-hex-3-yn-2-yl, 3methylpent-1yn-1yl, 3-methylpent-1-yn-3-yl,3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl,4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

The term “haloalkyl” refers to an alkyl group, as defined herein, whichis substituted by one or more halogen atoms. For example C₁-C₄-haloalkylincludes, but is not limited to, chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl andthe like.

The term “fluoroalkyl” as used herein refers to an alkyl in which one ormore of the hydrogen atoms is replaced with fluorine atoms, for exampledifluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl orpentafluoroethyl.

The term “haloalkenyl” refers to an alkenyl group, as defined herein,which is substituted by one or more halogen atoms.

The term “haloalkynyl” refers to an alkynyl group, as defined herein,which is substituted by one or more halogen atoms.

“Alkoxy” refers to alkyl-O—, wherein alkyl is as defined above.Similarly, the terms “alkenyloxy,” “alkynyloxy,” “haloalkoxy,”“haloalkenyloxy,” “haloalkynyloxy,” “cycloalkoxy,” “cycloalkenyloxy,”“halocycloalkoxy,” and “halocycloalkenyloxy” refer to the groupsalkenyl-O—, alkynyl-O—, haloalkyl-O—, haloalkenyl-O—, haloalkynyl-O—,cycloalkyl-O—, cycloalkenyl-O—, halocycloalkyl-O—, andhalocycloalkenyl-O—, respectively, wherein alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, andhalocycloalkenyl are as defined above. Examples of C₁-C₆-alkoxy include,but are not limited to, methoxy, ethoxy, OCH₂—C₂H₅, OCH(CH₃)₂, n-butoxy,OCH(CH₃)—C₂H₅, OCH₂—CH(CH₃)₂, OC(CH₃)₃, n-pentoxy, 1-methylbutoxy,2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy,1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxyand the like.

“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring or multiple fused rings. Aryl groupsinclude, but are not limited to, phenyl, biphenyl, and naphthyl. In someembodiments aryl includes tetrahydronaphthyl, phenylcyclopropyl andindanyl. Aryl groups may be unsubstituted or substituted by one or moremoieties selected from halogen, cyano, nitro, hydroxy, mercapto, amino,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy,alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy,cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy,alkylthio, haloalkylthio, halothio, cycloalkylthio, halocycloalkylthio,alkylsulfinyl, alkenylsulfinyl, alkynyl-sulfinyl, haloalkyl sulfinyl,haloalkenyl sulfinyl, haloalkynyl sulfinyl, alkyl sulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl, haloalkenylsulfonyl,haloalkynylsulfonyl, —SF₅, alkylamino, alkenylamino, alkynylamino,di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, or trialkylsilyl.

The term “aralkyl” refers to an aryl group that is bonded to the parentcompound through a diradical alkylene bridge, (—CH₂—)_(m), where n is1-12 and where “aryl” is as defined above.

“Heteroaryl” refers to a monovalent aromatic group of from 1 to 15carbon atoms, preferably from 1 to 10 carbon atoms, having one or moreoxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfurheteroatoms may optionally be oxidized. Such heteroaryl groups can havea single ring (e.g., pyridyl or furyl) or multiple fused rings providedthat the point of attachment is through a heteroaryl ring atom. Examplesof heteroaryls include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, pyrrolyl, indolyl, quinolinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl benzofuranyl,benzothiophenyl, imidazopyridyl, imidazopyrimidyl, or pyrrolopyrimidyl.Heteroaryl rings may be unsubstituted or substituted by one or moremoieties as described for aryl above.

“Heterocyclyl,” “heterocyclic” or “heterocyclo” refers to fullysaturated or unsaturated, cyclic groups, for example, 3 to 7 memberedmonocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclicring systems, which have one or more oxygen, sulfur or nitrogenheteroatoms in ring, preferably 1 to 4 or 1 to 3 heteroatoms. Thenitrogen and sulfur heteroatoms may optionally be oxidized and thenitrogen heteroatoms may optionally be quaternized. Unless otherwiseindicated, the heterocyclic group may be attached at any heteroatom orcarbon atom of the ring or ring system and may be unsubstituted orsubstituted by one or more moieties as described for aryl groups above.

Exemplary monocyclic heterocyclic groups include, but are not limitedto, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl,oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl,oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl,thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl,tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include, but are not limited to,indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and the like.

The term “alkylthio” refers to alkyl-S—, where “alkyl” is as definedabove. In some embodiments, the alkyl component of the alkylthio groupwill include C₁-C₁₀, C₁-C₈, C₁-C₆ C₁-C₄ or C₁-C₃ alkyl groups. Forexample, C₁-C₄-alkylthio includes, but is not limited to, methylthio,ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio,2-methylpropylthio or 1,1-dimethylethylthio.

Similarly, the terms “haloalkylthio,” “cycloalkylthio,”“halocycloalkylthio” refer to the groups —S-haloalkyl, —S-cycloalkyl,and —S-halocycloalkyl, respectively, where the terms “haloalkyl,”“cycloalkyl,” and “halocycloalkyl” are as defined above.

The term “halothio” refers to groups of the formula X_(n)—S— where X isa halogen atom and n is 1, 3 or 5. The term “halothio” includes —SF₅.

The term “alkylsulfinyl” refers to the group alkyl-S(═O)—, where “alkyl”is as defined above. In some embodiments, the alkyl component inalkylsulfinyl groups will include C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₄ orC₁-C₃ alkyl groups. Examples include, but are not limited to, —SO—CH₃,—SO—C₂H₅, n-propylsulfinyl, 1-methyl ethyl sulfinyl, n-butylsulfinyl,1-methylpropylsulfinyl, 2-methylpropyl sulfinyl, 1,1-dimethyl ethylsulfinyl, n-pentylsulfinyl, 1-methylbutyl sulfinyl,2-methylbutylsulfinyl, 3-methylbutyl sulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentyl sulfinyl,4-methylpentylsulfinyl, 1, 1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutyl sulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropyl sulfinyl,1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

Similarly, the terms “alkenylsulfinyl,” “alkynylsulfinyl,”“haloalkylsulfinyl,” “haloalkenylsulfinyl,” and “haloalkynylsulfinyl”refer to the groups alkenyl-S(═O)—, alkynyl-S(═O)—, andhaloalkyl-S(═O)—, haloalkenyl-S(═O)—, and haloalkynyl-S(═O)—, where theterms “alkenyl,” “alkynyl,” “haloalkyl,” “haloalkenyl,” and“haloalkynyl” are as defined above.

The term “alkylsulfonyl” refers to the group alkyl-S(═O)₂—, where theterm “alkyl” is as defined above. In some embodiments, the alkylcomponent in alkylsulfonyl groups will include C₁-C₁₂, C₁-C₁₀, C₁-C₈,C₁-C₆ or C₁-C₄ alkyl groups. Examples include, but are not limited to,—SO₂—CH₃, —SO₂—C₂H₅, n-propylsulfonyl, —SO₂—CH(CH₃)₂, n-butylsulfonyl,1-methylpropyl sulfonyl, 2-methylpropyl sulfonyl, —SO₂—C(CH₃)₃, n-pentylsulfonyl, 1-methylbutyl sulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropyl sulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, n-hexyl sulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropyl sulfonyl,1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl and thelike.

The terms “alkenylsulfonyl,” “alkynylsulfonyl,” “haloalkylsulfonyl,”“haloalkenylsulfonyl,” and “haloalkynylsulfonyl” refer to the groupsalkenyl-S(═O)₂—, alkynyl-S(═O)₂—, and haloalkyl-S(═O)₂—,haloalkenyl-S(═O)₂—, and haloalkynyl-S(═O)₂—, where the terms “alkenyl,”“alkynyl,” “haloalkyl,” “haloalkenyl,” and “haloalkynyl” are as definedabove.

The terms “alkylamino,” “dialkylamino,” “alkenylamino,” “alkynylamino,”“di(alkenyl)amino,” and “di(alkynyl)amino” refer to the groups—NH(alkyl), —N(alkyl)₂, —NH(alkenyl), —NH(alkynyl), —N(alkenyl)₂ and—N(alkynyl)₂, where the terms “alkyl,” “alkenyl,” and “alkynyl” are asdefined above. In some embodiments, the alkyl component in alkylamino ordialkylamino groups will include C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆ or C₁-C₄alkyl groups.

Compounds of the Invention:

The compounds of the invention are 24-membered cyclic depsipeptidecompounds which have potent activity against endoparasites such asnematodes and filarial worms (microfilarial and larval stages) and alsoagainst ectoparasites such as fleas and ticks. In one embodiment theinvention provides cyclic depsipeptide compounds of formula (I), or apharmaceutically or veterinarily acceptable salt thereof:

wherein:

Cy¹ and Cy² are independently aryl, carbocyclic, heteroaryl orheterocyclic, each of which may be optionally substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl and heteroaryl, wherein each cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl substituents of Cy¹ andCy² is optionally further independently substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂;

R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthio, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, or the group —CH₂C(O)NHCH₂CF₃; or R⁵and R⁶ together with the atom(s) to which they are bonded form a C₃-C₆cyclic group;

R′, R″, R′″ and R″″ are each independently hydrogen or C₁-C₃alkyl;

R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl; and

(a) R¹ is a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring or R¹ is C₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein theC₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted by a 3- to 8-memberedcarbocyclic or 3- to 8-membered heterocyclic ring; wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring or 3- to8-membered carbocyclic or 3- to 8-membered heterocyclic ring may befurther independently substituted by one or more substituents selectedfrom the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino; and R¹ is hydrogen or C₁-C₃alkyl; or

R¹ and R^(1′) together form a 2-6-membered carbon chain to form a ring;and

R², R^(2′), R³, R^(3′), R⁴ and R^(4′) are each independently hydrogen orC₁-C₈ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(b) R² is a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring, or R² is C₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein theC₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted by a 3- to 8-memberedcarbocyclic or 3- to 8-membered heterocyclic ring; wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring or 3- to8-membered carbocyclic or 3- to 8-membered heterocyclic ring may befurther independently substituted by one or more substituents selectedfrom the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino; and R^(2′) is hydrogen or C₁-C₃alkyl; or

R² and R^(2′) together form a 2-6-membered carbon chain to form a ring;and

R¹, R^(1′), R³, R^(3′), R⁴ and R^(4′) are each independently hydrogen orC₁-C₈ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(c) R³ is a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring, or R³ is C₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein theC₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted by a 3-to 8-memberedcarbocyclic or 3- to 8-membered heterocyclic group; wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring or 3- to8-membered carbocyclic or 3- to 8-membered heterocyclic ring may befurther independently substituted by one or more substituents selectedfrom the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino; and R^(3′) is hydrogen or C₁-C₃alkyl; or

R³ and R^(3′) together form a 2-6-membered carbon chain to form a ring;and

R¹, R^(1′), R², R^(2′), R⁴ and R^(4′) are each independently hydrogen orC₁-C₈ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(d) R⁴ is a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring, or R⁴ is C₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein theC₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted by a 3-to 8-memberedcarbocyclic or 3- to 8-membered heterocyclic ring; wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring or 3- to8-membered carbocyclic or 3- to 8-membered heterocyclic ring may befurther independently substituted by one or more substituents selectedfrom the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, 5 amino,alkylamino and dialkylamino; and R^(4′) is hydrogen or C₁-C₃alkyl; or

R⁴ and R^(4′) together form a 2-6-membered carbon chain to form a ring;and

R¹, R^(1′), R², R^(2′), R³ and R^(3′) are each independently hydrogen orC₁-C₈ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(e) R¹ and/or R² are each independently a 3- to 6-membered carbocyclicor 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;wherein said 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring(s) may be further independently substituted by one ormore substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(2′) areindependently hydrogen or C₁-C₃alkyl; or

R¹ and R^(1′) together and/or R² and R^(2′) together independently forma 2-6-membered carbon chain to form a ring; and

R³, R^(3′), R⁴ and R^(4′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(f) R¹ and/or R³ are each independently a 3- to 6-membered carbocyclicor 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;wherein said 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring(s) may be further independently substituted by one ormore substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(3′) areindependently hydrogen or C₁-C₃alkyl; or

R¹ and R^(1′) together and/or R³ and R^(3′) together independently forma 2-6-membered carbon chain to form a ring; and

R², R^(2′), R⁴ and R^(4′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(g) R¹ and/or R⁴ are each independently a 3- to 6-membered carbocyclicor 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;wherein said 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring(s) may be further independently substituted by one ormore substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(4′) areindependently hydrogen or C₁-C₃alkyl; or

R¹ and R^(1′) together and/or R⁴ and R^(4′) together independently forma 2-6-membered carbon chain to form a ring; and

R², R^(2′), R³ and R^(3′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(h) R² and/or R⁴ are each independently a 3- to 6-membered carbocyclicor 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;wherein said 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring(s) may be further independently substituted by one ormore substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(2′) and/or R^(4′) areindependently hydrogen or C₁-C₃alkyl; or

R² and R^(2′) together and/or R⁴ and R^(4′) together independently forma 2-6-membered carbon chain to form a ring; and

R¹, R^(1′), R³ and R^(3′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(i) R² and/or R³ are each independently a 3- to 6-membered carbocyclicor 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;wherein said 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring(s) may be further independently substituted by one ormore substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(2′) and/or R^(3′) areindependently hydrogen or C₁-C₃alkyl; or

R² and R^(2′) together and/or R³ and R^(3′) together independently forma 2-6-membered carbon chain to form a ring; and

R¹, R^(1′), R⁴ and R^(4′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(j) R³ and/or R⁴ are each independently a 3- to 6-membered carbocyclicor 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 8-membered carbocyclic or 3- to 8-membered heterocyclic ring;wherein said 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring(s) may be further independently substituted by one ormore substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(3′) and/or R^(4′) areindependently hydrogen or C₁-C₃alkyl; or

R³ and R^(3′) together and/or R⁴ and R^(4′) together independently forma 2-6-membered carbon chain to form a ring; and

R¹, R^(1′), R² and R^(2′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or

(k) R¹ and/or R² and/or R³ are each independently a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl orC₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(2′)and/or R^(3′) are independently hydrogen or C₁-C₃alkyl; or

R¹ and R^(1′) together and/or R² and R^(2′) together and/or R³ andR^(3′) together independently form a 2-6-membered carbon chain to form aring; and

R⁴ and R^(4′) are independently hydrogen or C₁-C₈ alkyl, optionallysubstituted by one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino; or

(1) R² and/or R³ and/or R⁴ are each independently a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl orC₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(2′) and/or R^(3′)and/or R^(4′) are independently hydrogen or C₁-C₃alkyl; or

R² and R^(2′) together and/or R³ and R^(3′) together and/or R⁴ andR^(4′) together independently form a 2-6-membered carbon chain to form aring; and

R¹ and R^(1′) are independently hydrogen or C₁-C₈ alkyl, optionallysubstituted by one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino; or

(m) R¹ and/or R³ and/or R⁴ are each independently a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl orC₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(3′)and/or R^(4′) are independently hydrogen or C₁-C₃alkyl; or

R¹ and R^(1′) together and/or R³ and R^(3′) together and/or R⁴ andR^(4′) together independently form a 2-6-membered carbon chain to form aring; and

R² and R^(2′) are independently hydrogen or C₁-C₈ alkyl, optionallysubstituted by one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino; or

(n) R¹ and/or R² and/or R⁴ are each independently a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl orC₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino and alkylamino and dialkylamino; and R^(1′) and/or R^(2′)and/or R^(4′) are independently hydrogen or C₁-C₃alkyl; or

R¹ and R^(1′) together and/or R² and R^(2′) together and/or R⁴ andR^(4′) together independently form a 2-6-membered carbon chain to form aring; and

R³ and R^(3′) are independently hydrogen or C₁-C₈ alkyl, optionallysubstituted by one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino; or

(o) R¹ and/or R² and/or R³ and/or R⁴ are each independently a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(2′)and/or R^(3′) and/or R^(4′) are independently hydrogen or C₁-C₃alkyl; or

R¹ and R^(1′) together and/or R² and R^(2′) together and/or R³ andR^(3′) together and/or R⁴ and R^(4′) together independently form a2-6-membered carbon chain to form a ring.

Cy¹ and Cy² Groups

In one embodiment, Cy¹ and Cy² are independently phenyl substituted withone or more substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl and heteroaryl, wherein each cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl substituent is optionallyfurther independently substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂; where R⁵ and R⁶ are as definedabove. It will be appreciated that the substituents on the phenyl ringmay be at any position of the ring including at the ortho, meta and parapositions to the point of attachment to the macrocycle.

In another embodiment, Cy¹ and Cy² are independently phenyl, heteroarylor heterocyclyl optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl and heteroaryl, wherein each cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl substituent is optionallyfurther independently substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.

In another embodiment, Cy¹ and Cy² are independently 6-12 memberedbicyclic aryl, 6-12 membered bicyclic heteroaryl or 6-12 memberedbicyclic heterocyclyl groups, each of which is optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,cycloalkyl, heteroalkyl, heterocyclyl, aryl and heteroaryl, wherein eachcycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl substituent isoptionally further independently substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.

In another embodiment, Cy¹ and Cy² are independently bicyclicheterocyclic groups, each of which is optionally substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl,heteroalkyl, heterocyclyl, aryl and heteroaryl substituent is optionallyfurther independently substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.

In another embodiment, Cy¹ and Cy² are independently phenyl, biphenyl,naphthyl, tetrahydronaphthyl, phenylcyclopropyl, biphenylene(biphenylenyl), fluorene (fluorenyl), anthracene (anthracenyl),acenaphthene (acenaphthenyl), phenanthrene (phenanthrenyl) or indanyl,each of which optionally substituted with one or more substituentsselected from the group consisting of halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino,dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—,R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl,heterocyclyl, aryl and heteroaryl, wherein each cycloalkyl, heteroalkyl,heterocyclyl, aryl or heteroaryl substituent is optionally furtherindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂.

In yet another embodiment, Cy¹ and Cy² are independently pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl,thiophenyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, benzoxazolyl, benzothiazolyl, pyrazolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl, imidazopyridyl, imidazopyrimidylor pyrrolopyrimidyl, each of which is optionally substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl and heteroaryl, wherein each cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl substituent is optionallyfurther independently substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.

In another embodiment, Cy¹ and Cy² are independently pyrrolidinyl,pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyl,each of which is optionally independently substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl and heteroaryl, wherein each cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl substituent is optionallyfurther independently substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.

In another embodiment, Cy¹ and Cy² are independently indolyl,isoindolyl, benzothiazolyl, benzoxazolyl, benz[d]isoxazolyl,benzotriazolyl, benzodioxolyl, benzothienyl, quinuclidinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl,coumarinyl, cinnolinyl, indazolyl, pyrrolopyridyl, phthalazinyl,1,2,3-benzotriazinyl, 1,2,4-benzotriazinyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl ortetrahydroisoquinolinyl, each of which is optionally substituted withone or more substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl substituent is optionallyfurther independently substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.

In one embodiment, Cy¹ and Cy² are independently phenyl substituted withheterocyclyl. In yet another embodiment, Cy¹ and Cy² are independently a6-membered heteroaryl group substituted with heterocyclyl. In stillanother embodiment, Cy¹ and Cy² are independently heterocyclylsubstituted with a heterocyclyl group. In yet another embodiment, Cy¹and Cy² are independently phenyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl or tetrazinyl, each of which is substituted with heterocyclyl.

In one embodiment, Cy¹ and Cy² are independently phenyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl or tetrazinyl, each of which issubstituted with morpholino, tetrahydropyran, tetrahydrofuran,pyrrolidino or piperidino, wherein said morpholino, tetrahydropyran,tetrahydrofuran, pyrrolidino or piperidino may be optionally substitutedwith one or more halogen, alkyl or haloalkyl.

In one embodiment, Cy¹ and Cy² are independently phenyl or a 5-memberedor a 6-membered heteroaryl ring, each of which is optionally substitutedwith one or more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, —SF₅, amino, alkylamino or dialkylamino.

In another embodiment, Cy¹ and Cy² are independently phenyl or a5-membered or a 6-membered heteroaryl ring, each of which is optionallysubstituted with one or more alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl.

In another embodiment, Cy¹ and Cy² are independently phenyl or a5-membered or a 6-membered heteroaryl ring, each of which is optionallysubstituted with one or more methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, CF₃, —CH₂CF₃, —CHFCF₃ or —CF₂CF₃.

In another embodiment, Cy¹ and Cy² are independently phenyl or a5-membered or a 6-membered heteroaryl ring, each of which is optionallysubstituted with fluoro, chloro, bromo or iodo.

In another embodiment, Cy¹ and Cy² are independently phenyl or a5-membered or a 6-membered heteroaryl ring, each of which is optionallysubstituted with one or more hydroxy, methoxy, trifluoromethoxy,—OCH₂CF₃, —OCHFCF₃, —OCF₂CF₃, —SCH₃, —SCF₃, —SCH₂CF₃, —SCHFCF₃,—SCF₂CF₃, —S(O)CH₃, —S(O)CF₃, —S(O)CH₂CF₃, —S(O)CHFCF₃, —S(O)CF₂CF₃,—S(O)₂CH₃, —S(O)₂CF₃, —S(O)₂CH₂CF₃, —S(O)₂CHFCF₃, —S(O)₂CF₂CF₃ or SF₅.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, thiazolyl, isothiazolyl, 1,3-4-thiadazolyl,pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl or tetrazinyl, each of which is optionallysubstituted with one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino or dialkylamino.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, thiazolyl, isothiazolyl, 1,3-4-thiadazolyl,pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl or tetrazinyl, each of which is optionallysubstituted with one or more alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl or haloalkynyl.

In another embodiment, Cy¹ and Cy² are independently phenyl, a5-membered or a 6-membered heteroaryl ring, each of which is optionallysubstituted with methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, CF₃, —CH₂CF₃, —CHFCF₃ or —CF₂CF₃.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, thiazolyl, isothiazolyl, 1,3-4-thiadazolyl,pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl or tetrazinyl, each of which is optionallysubstituted with fluoro, chloro, bromo or iodo.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, thiazolyl, isothiazolyl, 1,3-4-thiadazolyl,pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl or tetrazinyl, each of which is optionallysubstituted with hydroxy, methoxy, trifluoromethoxy, —OCH₂CF₃, —OCHFCF₃,—OCF₂CF₃, —SCH₃, —SCF₃, —SCH₂CF₃, —SCHFCF₃, —SCF₂CF₃, —S(O)CH₃,—S(O)CF₃, —S(O)CH₂CF₃, —S(O)CHFCF₃, —S(O)CF₂CF₃, —S(O)₂CH₃, —S(O)₂CF₃,—S(O)₂CH₂CF₃, —S(O)₂CHFCF₃, —S(O)₂CF₂CF₃ or SF₅.

In another embodiment, Cy¹ and Cy² are independently phenyl substitutedby C₁-C₆alkyl, C₁-C₆-haloalkyl, C₁-C₃alkoxy, C₁-C₃-haloalkoxy,C₃-C₈cycloalkyl, tetrahydropyranyl, morpholinyl or piperidinyl, whereineach C₁-C₆alkyl, C₃-C₈cycloalkyl, tetrahydropyranyl, morpholinyl orpiperidinyl is optionally substituted by one or more halogen,C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy or SF₅.

In another embodiment, Cy¹ and Cy² are independently phenyl substitutedby t-butyl, sec-butyl, isobutyl, isopropyl, trifluoromethyl, methoxy,ethoxy, propoxy, trifluoromethoxy, cyclopentyl, cyclohexyl,tetrahydropyranyl, morpholinyl or piperidinyl, wherein each t-butyl,sec-butyl, isobutyl, isopropyl, cyclopentyl, cyclohexyl,tetrahydropyranyl, morpholinyl or piperidinyl is optionally substitutedby one or more halogen, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy or SF₅.

In another embodiment, Cy¹ and Cy² are independently phenyl substitutedby t-butyl, isopropyl, cyclohexyl, trifluoromethoxy, trifluoromethyl,tetrahydropyranyl, morpholinyl or piperidinyl, wherein each cyclohexyl,tetrahydropyranyl, morpholinyl or piperidinyl is optionally substitutedby one or more halogen, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy or SF₅.

In another embodiment, Cy¹ and Cy² are independently phenyl substitutedby t-butyl, trifluoromethyl, trifluoromethoxy, cyclohexyl,tetrahydropyranyl, morpholinyl or piperidinyl, wherein each cyclohexyl,tetrahydropyranyl, morpholinyl or piperidinyl is optionally substitutedby one or more fluoro.

In another embodiment, Cy¹ and Cy² are independently one of R1 to R8shown below:

wherein Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C,CH or N; and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen,oxo, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,cycloalkyl, heteroalkyl, aryl or heteroaryl, wherein each cycloalkyl,heteroalkyl, aryl or heteroaryl substituent is optionally furthersubstituted with one or more substituents selected from the groupconsisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂, where R⁵ and R⁶ are as defined above; and thedashed lines together with the solid lines, i.e.

represents single or double bonds.

In one embodiment, Cy¹ and Cy² are independently R1 to R8 wherein Y¹,Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N; andX¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, thioamido, amino, alkylamino or dialkylamino.

In another embodiment, Cy¹ and Cy² are independently R1 to R8 whereinY¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N;and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl.

In another embodiment, Cy¹ and Cy² are independently R1 to R8 whereinY¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N;and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, CF₃, —CH₂CF₃,—CHFCF₃ or CF₂CF₃.

In another embodiment, Cy¹ and Cy² are independently R1 to R8 whereinY¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N;and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, fluoro,chloro, bromo or iodo.

In another embodiment, Cy¹ and Cy² are independently R1 to R8, whereinY¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N;and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, hydroxy,methoxy, trifluoromethoxy, —OCH₂CF₃, —OCHFCF₃, —OCF₂CF₃, methylthio,trifluoromethylthio, —SCH₂CF₃, —SCHFCF₃, —SCF₂CF₃ or SF₅.

In another embodiment, Cy¹ and Cy² are independently R9 to R11 shownbelow:

wherein X¹, X² and X³ are independently hydrogen, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, aryl or heteroaryl, wherein R⁵ and R⁶ are as defined above,and wherein each cycloalkyl, heteroalkyl, aryl or heteroaryl isoptionally further substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.

In one embodiment, Cy¹ and Cy² are independently R9 to R11, wherein X¹,X² and X³ are independently hydrogen, halogen, alkyl or haloalkyl. Inanother embodiment, Cy¹ and Cy² are independently R9 to R11, wherein X¹,X² and X³ are independently hydrogen, fluoro, chloro, bromo or iodo. Inanother embodiment, Cy¹ and Cy² are independently R9 to R11, wherein X²and X³ are independently hydrogen, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, CF₃, —CH₂CF₃, —CHFCF₃ or CF₂CF₃. In yetanother embodiment, Cy¹ and Cy² are independently R9 to R11, wherein X¹,X² and X³ are independently hydrogen, hydroxy, methoxy,trifluoromethoxy, —OCH₂CF₃, —OCHFCF₃, —OCF₂CF₃, methylthio,trifluoromethylthio, —SCH₂CF₃, —SCHFCF₃, —SCF₂CF₃ or SF₅.

In another embodiment, Cy¹ and/or Cy² are independently phenyl,p-morpholinophenyl, p-fluorophenyl, p-OCF₃-phenyl, p-CF₃-phenyl,3,4,5-trifluoro-phenyl, p-tetrahydropyranyl-phenyl,4-morpholino-2-pyridinyl, 4-morpholino-3-pyridinyl,p-thiosulfonylmorpholino-phenyl, p-NH₂-phenyl, p-S-tetrazolyl-phenyl,p-NH₂-phenyl, dihydrobenzofuranyl, 4-morpholinocyclohexyl, p-iodophenyl,p-bromophenyl, p-nitrophenyl and p-tert-butylphenyl.

In another embodiment, Cy¹ and Cy² are the groups shown in Table 1below:

TABLE 1 Cy¹ Cy² p-F—Ph p-F—Ph Ph Ph p-CF₃—Ph p-CF₃—Ph 3,4,5-tri-F—Ph3,4,5-tri-F—Ph p-NH₂—Ph p-NH₂—Ph p-OCF₃—Ph p-OCF₃—Ph p-SCF₃—Ph p-SCF₃—Php-tBu—Ph p-tBu—Ph p-I—Ph p-I—Ph p-Br—Ph p-Br—Ph p-NO₂—Ph p-NO₂—Php-SF₅—Ph p-SF₅—Ph

Ph

p-I—Ph

Ph

R^(a) and R^(b)

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl. In one embodiment, R^(a) and R^(b) are independentlyhydrogen or methyl. In another embodiment, R^(a) and R^(b) areindependently hydrogen, methyl, ethyl or propyl. In another embodiment,R^(a) and R^(b) are independently hydrogen, methyl or CF₃. In stillanother embodiment, R^(a) and R^(b) are both methyl. In yet anotherembodiment, R^(a) and R^(b) are both hydrogen.

R′, R″, R′″ and R″″

In one embodiment, R′, R″, R′″ and R″″ are independently hydrogen orC₁-C₃alkyl. In another embodiment, R′, R″, R′″ and R″″ are independentlyhydrogen or methyl. In another embodiment, each of R′, R″, R′″ and R″″are independently hydrogen, methyl or ethyl.

R¹, R^(1′), R², R^(2′), R³, R^(3′) R⁴ and R^(4′)

It will be understood that the invention includes compounds wherein thevarious groups Cy¹ and Cy² described in the above embodiments arecombined with any combination of R¹, R^(1′), R², R^(2′), R³, R^(3′) R⁴and R^(4′) described above for formula (I) and in the embodimentsdescribed below.

In one embodiment of the invention, one of R¹ to R⁴ is a 3- to6-membered carbocyclic or a 3- to 6-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring may be further substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,halothio, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano,amino, alkylamino and dialkylamino; while the others of R¹ to R⁴ areindependently C₁-C₈ alkyl, optionally independently substituted by oneor more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In another embodiment, two of R¹ to R⁴ are independently a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; while theother two of R¹ to R⁴ are independently C₁-C₈ alkyl, optionallyindependently substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In another embodiment, R² and R⁴ are independently a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃ alkyl orC₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R¹ andR³ are independently C₁-C₈ alkyl, optionally independently substitutedby one or more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino. In another embodiment, R¹ and R³ areindependently a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring, or C₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃alkyl or C₁-C₃ haloalkyl is substituted by a 3- to 8-memberedcarbocyclic or 3- to 8-membered heterocyclic ring; wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring(s) or 3- to8-membered carbocyclic or 3- to 8-membered heterocyclic ring(s) may befurther independently substituted by one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkyl, haloalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently C₁-C₈alkyl, optionally independently substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino or dialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; while theother of R¹ to R⁴ is C₁-C₈ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In still another embodiment, all four of R¹ to R⁴ are independently a 3-to 6-membered carbocyclic or 3- to 6-membered heterocyclic ring, orC₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃haloalkyl is substituted by a 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 6-membered carbocyclicor heterocyclic ring(s) or 3- to 8-membered carbocyclic or heterocyclicring(s) may be further independently substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In one embodiment of the invention, one of R¹ to R⁴ is a 3- to5-membered carbocyclic or 3- to 5-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 5-membered carbocyclic or 3- to5-membered heterocyclic ring or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring may be further substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,halothio, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano,amino, alkylamino and dialkylamino; while the others of R¹ to R⁴ areindependently C₁-C₈ alkyl, optionally independently substituted by oneor more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In another embodiment, two of R¹ to R⁴ are independently a 3- to5-membered carbocyclic or 3- to 5-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 5-membered carbocyclic or 3- to5-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; while theother two of R¹ to R⁴ are independently C₁-C₈ alkyl, optionallyindependently substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In another embodiment, R² and R⁴ are independently a 3- to 5-memberedcarbocyclic or 3- to 5-membered heterocyclic ring, or C₁-C₃ alkyl orC₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 5-membered carbocyclic or 3- to5-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R¹ andR³ are independently C₁-C₈ alkyl, optionally independently substitutedby one or more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino.

In yet another embodiment, R¹ and R³ are independently a 3- to5-membered carbocyclic or 3- to 5-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 5-membered carbocyclic or 3- to5-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R² andR⁴ are independently C₁-C₈ alkyl, optionally independently substitutedby one or more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently a 3- to5-membered carbocyclic or 3- to 5-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 5-membered carbocyclic or 3- to5-membered heterocyclic ring(s) or 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; while theother of R¹ to R⁴ is C₁-C₈ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In still another embodiment, all four of R¹ to R⁴ are independently a 3-to 5-membered carbocyclic or 3- to 5-membered heterocyclic ring, orC₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃haloalkyl is substituted by a 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 5-membered carbocyclicor 3- to 5-membered heterocyclic ring(s) or 3- to 8-membered carbocyclicor 3- to 8-membered heterocyclic ring(s) may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In another embodiment of the invention, one of R¹ to R⁴ is a 3- or4-membered carbocyclic or 3- or 4-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring; wherein said 3- or 4-membered carbocyclic or 3- or4-membered heterocyclic ring or 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring may be further substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; while the others of R¹ to R⁴are independently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino.

In another embodiment, two of R¹ to R⁴ are independently a 3- or4-membered carbocyclic or 3- or 4-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring; wherein said 3- or 4-membered carbocyclic or 3- or4-membered heterocyclic ring(s) or 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; while theother two of R¹ to R⁴ are independently C₁-C₆ alkyl, optionallysubstituted by one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In another embodiment, R² and R⁴ are independently a 3- or 4-memberedcarbocyclic or 3- or 4-membered heterocyclic ring, or C₁-C₃ alkyl orC₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring; wherein said 3- or 4-membered carbocyclic or 3- or4-membered heterocyclic ring(s) or 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R¹ andR³ are independently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino.

In still another embodiment, R¹ and R³ are independently a 3- or4-membered carbocyclic or 3- or 4-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring; wherein said 3- or 4-membered carbocyclic or 3- or4-membered heterocyclic ring(s) or 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R² andR⁴ are independently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently a 3- or4-membered carbocyclic or 3- or 4-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic ring; wherein said 3- or 4-membered carbocyclic or 3- or4-membered heterocyclic ring(s) or 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; while theother of R¹ to R⁴ is C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino.

In still another embodiment, all four of R¹ to R⁴ are independently a 3-or 4-membered carbocyclic or 3- or 4-membered heterocyclic ring, orC₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃haloalkyl is substituted by a 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring; wherein said 3- or 4-membered carbocyclicor 3- or 4-membered heterocyclic ring(s) or 3- to 6-membered carbocyclicor 3- to 6-membered heterocyclic ring(s) may be further substituted byone or more substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, one of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2-6-membered carbon chain toform a ring which is optionally substituted by one or more halogen,C₁-C₃alkyl or C₁-C₃haloalkyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogenor C₁-C₆ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, two of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2-6-membered carbon chain toform a ring which is optionally substituted by one or more halogen,C₁-C₃alkyl or C₁-C₃haloalkyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogenor C₁-C₆ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, R² and R⁴ together with thecorresponding R^(2′) and R^(4′) independently form a 2-6-membered carbonchain to form a ring which is optionally substituted by one or morehalogen, C₁-C₃alkyl or C₁-C₃haloalkyl; and

R¹, R^(1′), R³ and R^(3′) are independently hydrogen or C₁-C₆ alkyl,optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, R¹ and R³ together with thecorresponding R^(1′) and R^(3′) independently form a 2-6-membered carbonchain to form a ring which is optionally substituted by one or morehalogen, C₁-C₃alkyl or C₁-C₃haloalkyl; and

R², R^(2′), R⁴ and R^(4′) are independently hydrogen or C₁-C₆ alkyl,optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, three of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2-6-membered carbon chain toform a ring which is optionally substituted by one or more halogen,C₁-C₃alkyl or C₁-C₃haloalkyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogenor C₁-C₆ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, all four of R¹ to R⁴ togetherwith the corresponding R^(1′) to R^(4′) form a 2-6-membered carbon chainto form a ring which is optionally substituted by one or more halogen,C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment of the invention, one of R¹ to R⁴ is acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl ring or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 5-membered carbocyclic or 3- to 5-memberedheterocyclic ring, wherein said cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or phenyl ring or 3- to 5-membered carbocyclic or 3- to5-membered heterocyclic ring may be further group substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; while the others of R¹ to R⁴are independently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In another embodiment, two of R¹ to R⁴ are independently cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or phenyl or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 5-membered carbocyclic or 3- to 5-membered heterocyclic ring,wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenylring(s) or 3- to 5-membered carbocyclic or 3- to 5-membered heterocyclicring(s) may be further independently substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; while the other two of R¹ toR⁴ are independently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In another embodiment, R² and R⁴ are independently cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or phenyl or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 5-membered carbocyclic or 3- to 5-membered heterocyclic ring,wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenylring(s) or 3- to 5-membered carbocyclic or 3- to 5-membered heterocyclicring(s) may be further independently substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R¹ and R³ areindependently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In yet another embodiment, R¹ and R³ are independently cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or phenyl or C₁-C₃ alkyl or C₁-C₃haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted bya 3- to 5-membered carbocyclic or 3- to 5-membered heterocyclic ring,wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenylring(s) or 3- to 5-membered carbocyclic or 3- to 5-membered heterocyclicring(s) may be further independently substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R² and R⁴ areindependently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In another embodiment, R² and R⁴ are independently cyclopropyl,cyclobutyl, or phenyl; and R² and R³ are independently C₁-C₆ alkyl,optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In another embodiment, R¹ and R³ are independently cyclopropyl,cyclobutyl, or phenyl; and R² and R⁴ are independently C₁-C₆ alkyl,optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 5-membered carbocyclic or 3- to 5-memberedheterocyclic ring, wherein said cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or phenyl ring(s) or 3- to 5-membered carbocyclic or 3- to5-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting ofhalogen, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; while theother of R¹ to R⁴ is C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In still another embodiment, all four of R¹ to R⁴ are independentlycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 5-membered carbocyclic or 3- to 5-memberedheterocyclic ring, wherein said cyclopropyl ring(s) or 3- to 5-memberedcarbocyclic or 3- to 5-membered heterocyclic ring(s) may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In another embodiment of the invention, one of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2-4-membered carbon chain toform a cyclopropyl, cyclobutyl or cyclopentyl ring, each of which isoptionally substituted by one or more fluoro, methyl or trifluoromethyl;and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogenor C₁-C₆ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, two of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2-4-membered carbon chain toform a cyclopropyl, cyclobutyl or cyclopentyl ring, each of which isoptionally substituted by one or more fluoro, methyl or trifluoromethyl;and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogenor C₁-C₆ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, three of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2-4-membered carbon chain toform a cyclopropyl, cyclobutyl or cyclopentyl ring, each of which isoptionally substituted by one or more fluoro, methyl or trifluoromethyl;and

the other R¹ to R⁴ and corresponding R^(1′) to R^(4′) are independentlyhydrogen or C₁-C₆ alkyl, optionally substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, one of R¹ to R⁴ is a methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group (in otherwords methyl or methyl substituted by one or two halogen atoms, which isfurther substituted by a 3- to 6-membered carbocyclic or a 3- to6-membered heterocyclic group), wherein said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; while the others of R¹ to R⁴ areindependently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In another embodiment, two of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group (in otherwords methyl or methyl substituted by one or two halogen atoms, each ofwhich is independently further substituted by a 3- to 6-memberedcarbocyclic or a 3- to 6-membered heterocyclic group), wherein said 3-to 6-membered carbocyclic or 3- to 6-membered heterocyclic group may befurther substituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; while the other two of R¹ to R⁴ areindependently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkyl sulfinyl, haloalkylsulfinyl, alkyl sulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.

In another embodiment, R² and R⁴ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, each of whichis independently further substituted by a 3- to 6-membered carbocyclicor a 3- to 6-membered heterocyclic group), wherein said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkyl sulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are independently C₁-C₆alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In another embodiment, R¹ and R³ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, each of whichis independently further substituted by a 3- to 6-membered carbocyclicor a 3- to 6-membered heterocyclic group), wherein said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkyl sulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently C₁-C₆alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by a 3- to6-membered 3- to 6-membered carbocyclic or 3- to 6-membered heterocyclicgroup (in other words methyl or methyl substituted by one or two halogenatoms, each of which is independently further substituted by a 3- to6-membered carbocyclic or a 3- to 6-membered heterocyclic group),wherein said 3- to 6-membered carbocyclic or 3- to 6-memberedheterocyclic group may be further independently substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; while the other of R¹ to R⁴is C₁-C₆ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In still another embodiment, all four of R¹ to R⁴ are independentlymethylene (—CH₂—) or methylene substituted by one or two halogen atoms(—CHX— or —CX₂— where X is halogen) which are independently substitutedby a 3- to 6-membered carbocyclic or 3- to 6-membered heterocyclic group(in other words methyl or methyl substituted by one or two halogenatoms, each of which is independently further substituted by a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group), whereinsaid 3- to 6-membered carbocyclic or 3- to 6-membered heterocyclic groupmay be further independently substituted by one or more substituentsselected from the group consisting of halogen, hydroxy, alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, one of R¹ to R⁴ is a methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which is substituted by a carbocyclic orheterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane,thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran, and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, which is further substituted byone of said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic group may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino while the others of R¹ to R⁴ are C₁-C₄ alkyl,optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In another embodiment, two of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane,oxetane, thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran, and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by said carbocyclic or heterocyclic groups), whereinsaid carbocyclic or heterocyclic group may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino while the others of R¹ to R⁴ are C₁-C₄alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment, R² and R⁴ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a carbocyclic orheterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane,thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran, and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by said carbocyclic or heterocyclic groups), whereinsaid carbocyclic or heterocyclic group may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are independently C₁-C₄alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment, R¹ and R³ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a carbocyclic orheterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane,thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran, and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by said carbocyclic or heterocyclic groups), whereinsaid carbocyclic or heterocyclic group may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently C₁-C₄alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane,oxetane, thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran, and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by said carbocyclic or heterocyclic groups), whereinsaid carbocyclic or heterocyclic group may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the others of R¹ to R⁴ are C₁-C₄alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In still another embodiment, all four of R¹ to R⁴ are independentlymethylene (—CH₂—) or methylene substituted by one or two halogen atoms(—CHX— or —CX₂— where X is halogen) which are independently substitutedby carbocyclic or heterocyclic group selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane,oxetane, thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran, and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by said carbocyclic or heterocyclic groups), whereinsaid carbocyclic or heterocyclic group may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In another embodiment of the invention, one of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2- or 3-membered carbon chainto form a cyclopropyl or cyclobutyl ring which is optionally substitutedby one or more fluoro, methyl or trifluoromethyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogenor C₁-C₄ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, two of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) independently form a 2- or 3-memberedcarbon chain to form a cyclopropyl or cyclobutyl ring each of which isoptionally substituted by one or more fluoro, methyl or trifluoromethyl;and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogenor C₁-C₄ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, three of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) independently form a 2- or 3-memberedcarbon chain to form a cyclopropyl or cyclobutyl ring, each of which isoptionally substituted by one or more fluoro, methyl or trifluoromethyl;and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogenor C₁-C₄ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, all four of R¹ to R⁴ togetherwith the corresponding R^(1′) to R^(4′) independently form a 2- or3-membered carbon chain to form a cyclopropyl or cyclobutyl ring, eachof which is optionally substituted by one or more fluoro, methyl ortrifluoromethyl.

In still another embodiment, one of R¹ to R⁴ is methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are substituted by carbocyclic or heterocyclic groupselected from the group consisting of naphthyl, indanyl, biphenyl,indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benz[d]isoxazolyl,benzotriazolyl, benzodioxolyl, benzothienyl, quinuclidinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl,coumarinyl, cinnolinyl, indazolyl, pyrrolopyridyl, phthalazinyl,1,2,3-benzotriazinyl, 1,2,4-benzotriazinyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl andtetrahydroisoquinolinyl (in other words methyl or methyl substituted byone or two halogen atoms, which is further substituted by one of saidcarbocyclic or heterocyclic groups), wherein said carbocyclic orheterocyclic group may be further independently substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino, while the others of R¹ to R⁴are C₁-C₄ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkyl sulfinyl,haloalkyl sulfinyl, alkyl sulfonyl, haloalkyl sulfonyl, alkoxyalkoxy,oxo, cyano, amino, alkylamino or dialkylamino.

In still another embodiment, two of R¹ to R⁴ is methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by carbocyclic orheterocyclic group selected from the group consisting of naphthyl,indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl,benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by said carbocyclic or heterocyclicgroups), wherein said carbocyclic or heterocyclic group may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the others of R¹ to R⁴ are C₁-C₄alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In still another embodiment, R² and R⁴ are methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by carbocyclic orheterocyclic group selected from the group consisting of naphthyl,indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl,benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by said carbocyclic or heterocyclicgroups), wherein said carbocyclic or heterocyclic group may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are independently C₁-C₄alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In still another embodiment, R¹ and R³ are methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by carbocyclic orheterocyclic group selected from the group consisting of naphthyl,indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl,benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by said carbocyclic or heterocyclicgroups), wherein said carbocyclic or heterocyclic group may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently C₁-C₄alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In still another embodiment, three of R¹ to R⁴ are independentlymethylene (—CH₂—) or methylene substituted by one or two halogen atoms(—CHX— or —CX₂— where X is halogen) which are independently substitutedby carbocyclic or heterocyclic group selected from the group consistingof naphthyl, indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl,benzoxazolyl, benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl,benzothienyl, quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by said carbocyclic or heterocyclicgroups), wherein said carbocyclic or heterocyclic group may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the other of R¹ to R⁴ are C₁-C₄alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.

In still another embodiment, all four of R¹ to R⁴ are independentlymethylene (—CH₂—) or methylene substituted by one or two halogen atoms(—CHX— or —CX₂— where X is halogen) which are independently substitutedby carbocyclic or heterocyclic group selected from the group consistingof naphthyl, indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl,benzoxazolyl, benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl,benzothienyl, quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by said carbocyclic or heterocyclicgroups), wherein said carbocyclic or heterocyclic group may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In another embodiment of the invention, one of R¹ to R⁴ is a methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, which isfurther substituted by a 3- to 6-membered carbocyclic or a 3- to6-membered heterocyclic group), wherein said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the others of R¹ to R⁴ areindependently 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group (in otherwords methyl or methyl substituted by one or two halogen atoms, each ofwhich is independently further substituted by said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic groups), wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group may befurther substituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino, while the other two of R¹ to R⁴ are independently2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, R² and R⁴ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, each of whichis independently further substituted by said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic groups), wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group may befurther substituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are independently2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, each of whichis independently further substituted by said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic groups), wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group may befurther substituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group (in otherwords methyl or methyl substituted by one or two halogen atoms, each ofwhich is independently further substituted by said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group), wherein said 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group may befurther independently substituted by one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkyl, haloalkyl,C₃-C₆cycloalkyl, heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the other of R¹ to R⁴ is2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment of the invention, one of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2- or 3-membered carbon chainto form a cyclopropyl or cyclobutyl ring which is optionally substitutedby one or more fluoro, methyl or trifluoromethyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogen,2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment of the invention, two of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) independently form a 2- or 3-memberedcarbon chain to form a cyclopropyl or cyclobutyl ring, each of which isoptionally independently substituted by one or more fluoro, methyl ortrifluoromethyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogen,2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment of the invention, three of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) independently form a 2- or 3-memberedcarbon chain to form a cyclopropyl or cyclobutyl ring, each of which isoptionally independently substituted by one or more fluoro, methyl ortrifluoromethyl; and

the other of R¹ to R⁴ and the corresponding R^(1′) to R^(4′) areindependently hydrogen, 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment of the invention, one of R¹ to R⁴ is a methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which is substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, which isfurther substituted by a 3- to 6-membered carbocyclic or a 3- to6-membered heterocyclic group), wherein said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the others of R¹ to R⁴ areindependently 2,2-dimethylpropyl or 2-methylpropyl substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino.

In another embodiment, two of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic group (in otherwords methyl or methyl substituted by one or two halogen atoms, each ofwhich is independently further substituted by a 3- to 6-memberedcarbocyclic or a 3- to 6-membered heterocyclic group), wherein said 3-to 6-membered carbocyclic or 3- to 6-membered heterocyclic groups may befurther substituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino, while the other two of R¹ to R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment, R² and R⁴ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, each of whichis independently further substituted by a 3- to 6-membered carbocyclicor a 3- to 6-membered heterocyclic group), wherein said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic groups may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment, R¹ and R³ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, each of whichis independently further substituted by a 3- to 6-membered carbocyclicor a 3- to 6-membered heterocyclic group), wherein said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic groups may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by a 3- to6-membered carbocyclic or a 3- to 6-membered heterocyclic group, whereinsaid 3- to 6-membered carbocyclic or 3- to 6-membered heterocyclicgroups may be further independently substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkyl, haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl, heteroaryl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino, while the other of R¹ to R⁴is 2,2-dimethylpropyl or 2-methylpropyl substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In yet another embodiment, one of R¹ to R⁴ is methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which is substituted by a carbocyclic or heterocyclicgroup selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane, thiirane,thietane, aziridine, azetidine, pyrrolidine, pyrrole, thiophene,oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, which is independently furthersubstituted by said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic group may be further substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino, while theothers of R¹ to R⁴ are independently 2,2-dimethylpropyl or2-methylpropyl substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In yet another embodiment, two of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane,oxetane, thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, which is independently furthersubstituted by said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic groups may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the others of R¹ to R⁴ areindependently 2,2-dimethylpropyl or 2-methylpropyl substituted by one ormore halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino.

In yet another embodiment, R² and R⁴ are independently methylene (—CH₂—)or methylene substituted by one or two halogen atoms (—CHX— or —CX₂—where X is halogen) which are independently substituted by a carbocyclicor heterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane,thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, which is independently furthersubstituted by said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic groups may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino.

In yet another embodiment, R¹ and R³ are independently methylene (—CH₂—)or methylene substituted by one or two halogen atoms (—CHX— or —CX₂—where X is halogen) which are independently substituted by a carbocyclicor heterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane,thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, which is independently furthersubstituted by said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic groups may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane,oxetane, thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, which is independently furthersubstituted by said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic groups may be further independentlysubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the other R¹ to R⁴ is2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino or dialkylamino.

In yet another embodiment, one of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which is substituted by a carbocyclic orheterocyclic group selected from the group consisting of naphthyl,indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl,benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, which isindependently further substituted by one of said carbocyclic orheterocyclic groups), wherein said carbocyclic or heterocyclic group maybe further substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino, while the others of R¹ to R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino.

In another embodiment, two of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofnaphthyl, indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl,benzoxazolyl, benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl,benzothienyl, quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by one of said carbocyclic orheterocyclic groups), wherein said carbocyclic or heterocyclic groupsmay be further independently substituted by one or more substituentsselected from the group consisting of halogen, hydroxy, alkyl,haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino, while the others of R¹ to R⁴are independently 2,2-dimethylpropyl or 2-methylpropyl substituted byone or more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino.

In another embodiment, R² and R⁴ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a carbocyclic orheterocyclic group selected from the group consisting of naphthyl,indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl,benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by one of said carbocyclic orheterocyclic groups), wherein said carbocyclic or heterocyclic groupsmay be further independently substituted by one or more substituentsselected from the group consisting of halogen, hydroxy, alkyl,haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R¹ and R³ areindependently 2,2-dimethylpropyl or 2-methylpropyl substituted by one ormore halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino.

In another embodiment, R¹ and R³ are independently methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a carbocyclic orheterocyclic group selected from the group consisting of naphthyl,indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl,benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by one of said carbocyclic orheterocyclic groups), wherein said carbocyclic or heterocyclic groupsmay be further independently substituted by one or more substituentsselected from the group consisting of halogen, hydroxy, alkyl,haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R² and R⁴ areindependently 2,2-dimethylpropyl or 2-methylpropyl substituted by one ormore halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofnaphthyl, indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl,benzoxazolyl, benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl,benzothienyl, quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by one of said carbocyclic orheterocyclic groups), wherein said carbocyclic or heterocyclic groupsmay be further substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, phenyl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino, while theother R¹ to R⁴ is 2,2-dimethylpropyl or 2-methylpropyl substituted byone or more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino.

In another embodiment, all four of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofnaphthyl, indanyl, biphenyl, indolyl, isoindolyl, benzothiazolyl,benzoxazolyl, benz[d]isoxazolyl, benzotriazolyl, benzodioxolyl,benzothienyl, quinuclidinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, indazolyl,pyrrolopyridyl, phthalazinyl, 1,2,3-benzotriazinyl,1,2,4-benzotriazinyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and tetrahydroisoquinolinyl (in other words methylor methyl substituted by one or two halogen atoms, each of which isindependently further substituted by one of said carbocyclic orheterocyclic groups), wherein said carbocyclic or heterocyclic groupsmay be further substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In another embodiment of the invention, one of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2- or 3-membered carbon chainto form a cyclopropyl or cyclobutyl ring which is optionally substitutedby one or more fluoro, methyl or trifluoromethyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogen,2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, two of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) independently form a 2- or 3-memberedcarbon chain to form a cyclopropyl or cyclobutyl ring, each of which isoptionally independently substituted by one or more fluoro, methyl ortrifluoromethyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogen,2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino.

In another embodiment of the invention, three of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) independently form a 2- or 3-memberedcarbon chain to form a cyclopropyl or cyclobutyl ring, each of which isoptionally independently substituted by one or more fluoro, methyl ortrifluoromethyl; and

the other of R¹ to R⁴ and corresponding R^(1′) to R^(4′) areindependently hydrogen, 2,2-dimethylpropyl or 2-methylpropyl substitutedby one or more halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In yet another embodiment, one of R¹ to R⁴ is methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which is substituted by a carbocyclic or heterocyclicgroup selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane, thiirane,thietane, aziridine, azetidine, pyrrolidine, pyrrole, thiophene,oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, which is further substituted byone of said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic group may be further substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino, while theothers of R¹ to R⁴ are independently 2,2-dimethylpropyl or2-methylpropyl substituted by one or more halogen.

In yet another embodiment, two of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane,oxetane, thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by one of said carbocyclic or heterocyclic groups),wherein said carbocyclic or heterocyclic groups may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the others of R¹ to R⁴ areindependently 2,2-dimethylpropyl or 2-methylpropyl substituted by one ormore halogen.

In yet another embodiment, R² and R⁴ are independently methylene (—CH₂—)or methylene substituted by one or two halogen atoms (—CHX— or —CX₂—where X is halogen) which are independently substituted by a carbocyclicor heterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane,thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by one of said carbocyclic or heterocyclic groups),wherein said carbocyclic or heterocyclic groups may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen.

In yet another embodiment, R¹ and R³ are independently methylene (—CH₂—)or methylene substituted by one or two halogen atoms (—CHX— or —CX₂—where X is halogen) which are independently substituted by a carbocyclicor heterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane, oxetane,thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by one of said carbocyclic or heterocyclic groups),wherein said carbocyclic or heterocyclic groups may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxirane,oxetane, thiirane, thietane, aziridine, azetidine, pyrrolidine, pyrrole,thiophene, oxazole, isoxazole, isoxazoline, thiazole, isothiazole,1,3,4-thiadazole, pyrazole, imidazole, triazole, tetrazole, furan,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by one of said carbocyclic or heterocyclic groups),wherein said carbocyclic or heterocyclic groups may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, while the other of R¹ to R⁴ is2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen.

In yet another embodiment, one of R¹ to R⁴ is independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which is substituted by a carbocyclic orheterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxetane, pyrrole,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, which is further substituted byone of said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic group may be further substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino, while theothers of R¹ to R⁴ are independently 2,2-dimethylpropyl or2-methylpropyl substituted by one or more fluorine.

In yet another embodiment, two of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxetane,pyrrole, tetrahydrofuran and dihydrofuran (in other words methyl ormethyl substituted by one or two halogen atoms, each of which isindependently further substituted by one of said carbocyclic orheterocyclic groups), wherein said carbocyclic or heterocyclic groupsmay be further independently substituted by one or more substituentsselected from the group consisting of halogen, hydroxy, alkyl,haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino, while the others of R¹ to R⁴are independently 2,2-dimethylpropyl or 2-methylpropyl, substituted byone or more fluorine.

In yet another embodiment, R² and R⁴ are independently methylene (—CH₂—)or methylene substituted by one or two halogen atoms (—CHX— or —CX₂—where X is halogen) which are independently substituted by a carbocyclicor heterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxetane, pyrrole,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by one of said carbocyclic or heterocyclic groups),wherein said carbocyclic or heterocyclic groups may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are independently2,2-dimethylpropyl or 2-methylpropyl, substituted by one or morefluorine.

In yet another embodiment, R¹ and R³ are independently methylene (—CH₂—)or methylene substituted by one or two halogen atoms (—CHX— or —CX₂—where X is halogen) which are independently substituted by a carbocyclicor heterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxetane, pyrrole,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two halogen atoms, each of which is independentlyfurther substituted by one of said carbocyclic or heterocyclic groups),wherein said carbocyclic or heterocyclic groups may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl, substituted by one or morefluorine.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two halogen atoms (—CHX— or—CX₂— where X is halogen) which are independently substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxetane,pyrrole, tetrahydrofuran and dihydrofuran (in other words methyl ormethyl substituted by one or two halogen atoms, each of which isindependently further substituted by one of said carbocyclic orheterocyclic groups), wherein said carbocyclic or heterocyclic groupsmay be further independently substituted by one or more substituentsselected from the group consisting of halogen, hydroxy, alkyl,haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino, while the other of R¹ to R⁴is 2,2-dimethylpropyl or 2-methylpropyl substituted by one or morefluorine.

In yet another embodiment, one of R¹ to R⁴ is independently methylene(—CH₂—) or methylene substituted by one or two fluorine atoms (—CHF— or—CF₂—) which is substituted by a carbocyclic or heterocyclic groupselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, phenyl, oxetane, pyrrole, tetrahydrofuranand dihydrofuran (in other words methyl or methyl substituted by one ortwo fluorine atoms, which is further substituted by one of saidcarbocyclic or heterocyclic groups), wherein said carbocyclic orheterocyclic group may be further substituted by one or more halogen,C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, phenyl or oxo,while the others of R¹ to R⁴ are independently 2,2-dimethylpropyl or2-methylpropyl substituted by one or more fluorine.

In yet another embodiment, two of R¹ to R⁴ is independently methylene(—CH₂—) or methylene substituted by one or two fluorine atoms (—CHF— or—CF₂—) which are independently substituted by a carbocyclic orheterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxetane, pyrrole,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two fluorine atoms, each of which is independentlyfurther substituted by one of said carbocyclic or heterocyclic groups),wherein said carbocyclic or heterocyclic groups may be furtherindependently substituted by one or more halogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, phenyl or oxo, while theothers of R¹ to R⁴ are independently 2,2-dimethylpropyl or2-methylpropyl substituted by one or more fluorine.

In yet another embodiment, R² and R⁴ are independently methylene (—CH₂—)or methylene substituted by one or two fluorine atoms (—CHF— or —CF₂—)which are independently substituted by a carbocyclic or heterocyclicgroup selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, phenyl, oxetane, pyrrole, tetrahydrofuranand dihydrofuran (in other words methyl or methyl substituted by one ortwo fluorine atoms, each of which is independently further substitutedby one of said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic groups may be further independentlysubstituted by one or more halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₃alkoxy, C₁-C₃haloalkoxy, phenyl or oxo; and R¹ and R³ areindependently 2,2-dimethylpropyl or 2-methylpropyl substituted by one ormore fluorine.

In yet another embodiment, R¹ and R³ are independently methylene (—CH₂—)or methylene substituted by one or two fluorine atoms (—CHF— or —CF₂—)which are independently substituted by a carbocyclic or heterocyclicgroup selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, phenyl, oxetane, pyrrole, tetrahydrofuranand dihydrofuran (in other words methyl or methyl substituted by one ortwo fluorine atoms, each of which is independently further substitutedby one of said carbocyclic or heterocyclic groups), wherein saidcarbocyclic or heterocyclic groups may be further independentlysubstituted by one or more halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₃alkoxy, C₁-C₃haloalkoxy, phenyl or oxo; and R² and R⁴ areindependently 2,2-dimethylpropyl or 2-methylpropyl substituted by one ormore fluorine.

In yet another embodiment, three of R¹ to R⁴ are independently methylene(—CH₂—) or methylene substituted by one or two fluorine atoms (—CHF— or—CF₂—) which are independently substituted by a carbocyclic orheterocyclic group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxetane, pyrrole,tetrahydrofuran and dihydrofuran (in other words methyl or methylsubstituted by one or two fluorine atoms, each of which is independentlyfurther substituted by one of said carbocyclic or heterocyclic groups),wherein said carbocyclic or heterocyclic groups may be furtherindependently substituted by one or more halogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, phenyl or oxo, while theother of R¹ to R⁴ is 2,2-dimethylpropyl or 2-methylpropyl substituted byone or more fluorine.

In another embodiment of the invention, one of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) form a 2- or 3-membered carbon chainto form a cyclopropyl or cyclobutyl ring which is optionally substitutedby one or more fluoro, methyl or trifluoromethyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogen,2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In another embodiment of the invention, two of R¹ to R⁴ together withthe corresponding R^(1′) to R^(4′) independently form a 2- or 3-memberedcarbon chain to form a cyclopropyl or cyclobutyl ring, each of which isoptionally independently substituted by one or more fluoro, methyl ortrifluoromethyl; and

the others of R¹ to R⁴ and R^(1′) to R^(4′) are independently hydrogen,2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In another embodiment of the invention, three of R¹ to R⁴ together withthe corresponding R¹ to R⁴ independently form a 2- or 3-membered carbonchain to form a cyclopropyl or cyclobutyl ring, each of which isoptionally independently substituted by one or more fluoro, methyl ortrifluoromethyl; and

the other of R¹ to R⁴ and the corresponding R^(1′) to R^(4′) areindependently hydrogen, 2-methylpropyl substituted by one or morefluorine or 2,2-dimethylpropyl.

In one embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I) wherein one or both of R¹ and R³ areindependently selected from C₁-C₈ alkyl, optionally independentlysubstituted by one or more of: halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I) above, wherein one or both, preferably bothof R¹ and R³ are independently selected from C₂-C₆ alkyl, optionallyindependently substituted by one or more of halogen, preferably fluoro,chloro or iodo, more preferably fluoro or chloro and most preferablyfluoro.

In yet another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R¹ and R³ are both independentlyselected from C₃-C₅ alkyl independently substituted by one or more ofhalogen, preferably fluoro, chloro or iodo, more preferably fluoro orchloro and most preferably fluoro.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R¹ and R³ are both independentlyselected from C₃-C₅ alkyl substituted with one or more fluoro, andpreferably wherein R¹ and R³ are both independently selected from—CH₂—CF(CH₃)₂.

In another embodiment, the invention provides anthelmintic cyclicdepsipeptide of formula (I) above, wherein R¹ and R³ are the same.

In another embodiment, the invention provides anthelmintic cyclicdepsipeptide of formula (I), wherein one or both R^(1′) and R^(3′) are Hor alkyl, preferably H.

In yet another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R^(1′) and R^(3′) are the same, andpreferably both are H.

In yet another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein one or both of R² and R⁴ is a 3- to6-membered carbocyclic or 3- to 6-membered heterocyclic ring, or C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 6-membered carbocyclic orheterocyclic ring or 3- to 8-membered carbocyclic or heterocyclic ringmay be further substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, halothio,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In still another embodiment, the invention provides an anthelminticcyclic depsipeptide of formula (I), wherein one or both of R² and R⁴ isC₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃haloalkyl is substituted by a 3- to 8-membered carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 8-membered carbocyclicor heterocyclic ring may be further substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,halothio, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano,amino, alkylamino and dialkylamino.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein one or both of R² and R⁴ is C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 8-membered carbocyclic orheterocyclic ring may be further substituted by one or more substituentsselected from the group consisting of halogen, hydroxy, alkyl,haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, halothio, alkyl sulfonyl, haloalkylsulfonyl, oxo,cyano.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein one or both of R² and R⁴ is C₁-C₃alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by a 3- to 8-membered carbocyclic ring; wherein said 3- to8-membered carbocyclic ring may be further substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkyl, haloalkyl, alkoxy and haloalkoxy.

In still another embodiment, the invention provides an anthelminticcyclic depsipeptide of formula (I), wherein one or both of R² and R⁴ isC₁-C₃ alkyl or C₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃haloalkyl is substituted by a 3- to 6-membered carbocyclic ring; whereinsaid 3- to 6-membered carbocyclic ring may be further substituted by oneor more substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, alkoxy and haloalkoxy.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R² and R⁴ are each independentlyC₁-C₃ alkyl or C₁-C₃ haloalkyl, each of which are substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, phenyl, oxetane,pyrrole, tetrahydrofuran and dihydrofuran, wherein said carbocyclic orheterocyclic groups may be further substituted by one or more halogen,C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy, phenyl or oxo.

In another embodiment, provides is an anthelmintic cyclic depsipeptideof formula (I), wherein R² and R⁴ are each independently methyl,mono-fluoro substituted methyl or di-fluoro substituted methyl, each ofwhich are substituted by a carbocyclic or heterocyclic group selectedfrom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, phenyl, oxetane, pyrrole, tetrahydrofuran anddihydrofuran, wherein said carbocyclic or heterocyclic groups may befurther substituted by one or more halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₃alkoxy, C₁-C₃haloalkoxy, phenyl or oxo.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R² and R⁴ are each independentlymethyl, mono-fluoro substituted methyl or di-fluoro substituted methyl,each of which are substituted by a carbocyclic group selected from thegroup consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyland phenyl.

In yet another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R² and R⁴ are each independentlymethyl, mono-fluoro substituted methyl or di-fluoro substituted methyl,each of which are substituted by a carbocyclic group selected from thegroup consisting of cyclopropyl, cyclobutyl or cyclopentyl.

In another embodiment, provided is an anthelmintic cyclic depsipeptideof formula (I), wherein R² and R⁴ are each independently methyl,mono-fluoro substituted methyl or di-fluoro substituted methyl, each ofwhich is substituted by cyclopropyl.

In another embodiment, an anthelmintic cyclic depsipeptide of formula(I) is provided, wherein R² and R⁴ are each methyl which is substitutedby a 3-5 membered carbocyclic ring, preferably cyclopropyl, andpreferably wherein R² and R⁴ are each —CH₂-cyclopropyl.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R² and R⁴ are the same.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of any of formula (I), wherein one or both R^(1′) andR^(3′) are H or alkyl, preferably H.

In another embodiment, provided is an anthelmintic cyclic depsipeptideof formula (I), wherein R^(1′) and R^(3′) are the same, and preferablyboth are H.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R′, R″, R′″ and R″″ are eachindependently C₁-C₃alkyl, preferably methyl.

In another embodiment, the invention provides anthelmintic cyclicdepsipeptide of formula (I), wherein Cy¹ and Cy² are each independentlyselected from the group consisting of: phenyl substituted withheterocyclyl, preferably wherein the heterocyclyl is selected from thegroup consisting of: pyrrolidinyl, furyl, tetrahydrofuryl, thienyl,piperidinyl, piperazinyl and morpholinyl and more preferably wherein theheterocyclyl is morpholinyl.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein Cy¹ and Cy² are the same and areeach phenyl substituted with morpholinyl, preferably N-morpholinyl, andmore preferably para-N-morpholinylphenyl:

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein Cy¹ and Cy² are the same and areeach phenyl substituted with tetrahydropyranyl, preferablypara-tetrahydropyranyl, and more preferablypara-tetrahydropyranylphenyl:

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein R^(a) and R^(b) are independentlyC₁-C₃alkyl or C₁-C₃haloalkyl, preferably C₁-C₃alkyl and more preferablymethyl.

In another embodiment, the invention provides an anthelmintic cyclicdepsipeptide of formula (I), wherein:

R¹ and R³ are both independently selected from C₃-C₅ alkyl substitutedwith one or more fluoro, and preferably wherein R¹ and R³ are bothindependently selected from —CH₂—CF(CH₃)₂;

R² and R⁴ are each methyl which is substituted by a 3-5 memberedcarbocyclic ring, preferably cyclopropyl, and preferably wherein R² andR⁴ are each —CH₂-cyclopropyl;

R^(1′), R^(2′), R^(3′) and R^(4′) are H;

R′, R″, R′″ and R″″ are each independently C₁-C₃alkyl;

Cy¹ and Cy² are each independently selected from the group consistingof: phenyl substituted with heterocyclyl, preferably wherein theheterocyclyl is selected from the group consisting of: pyrrolidinyl,furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, piperidinyl,piperazinyl and morpholinyl; and

R^(a) and R^(b) are independently C₁-C₃alkyl.

In another embodiment, the invention provides anthelmintic cyclicdepsipeptide of formula (I), wherein:

R¹ and R³ are both independently selected from C₃-C₅ alkyl substitutedwith one or more fluoro, and preferably wherein R¹ and R³ are bothindependently selected from —CH₂—CF(CH₃)₂;

R² and R⁴ are each methyl which is substituted by a 3-5 memberedcarbocyclic ring, preferably cyclopropyl, and preferably wherein R² andR⁴ are each —CH₂-cyclopropyl;

R^(1′), R^(2′), R^(3′) and R^(4′) are H;

R′, R″, R′″ and R″″ are each independently C₁-C₃alkyl;

Cy¹ and Cy² are each independently selected from the group consistingof: phenyl substituted with heterocyclyl, preferably wherein theheterocyclyl is selected from the group consisting of: pyrrolidinyl,furyl, tetrahydrofuryl, thienyl, piperidinyl, piperazinyl andmorpholinyl; and

R^(a) and R^(b) are independently C₁-C₃alkyl.

In another embodiment of the invention, one, two or three of R¹ to R⁴are cyclopropyl, cyclobutyl, phenyl or oxetane, or methylene (—CH₂—) ormethylene substituted by one or two halogen atoms (—CHX— or —CX₂— whereX is halogen) which are independently substituted by a 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group (in other wordsmethyl or methyl substituted by one or two halogen atoms, each of whichis independently further substituted by a 3- to 6-membered carbocyclicor a 3- to 6-membered heterocyclic group), wherein said 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic group may be furtherindependently substituted by one or more substituents selected from thegroup consisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino, and the others of R¹ to R⁴ is the groupG-1:

wherein R^(1A), R^(1B), R^(1C), R^(1D) and R^(1E) are independentlyhydrogen, halogen, alkyl or haloalkyl.

In one embodiment, one, two or three of R¹ to R⁴ are independentlycyclopropyl or phenyl or methylene (—CH₂—) or methylene substituted byone or two halogen atoms (—CHX— or —CX₂— where X is halogen) which aresubstituted by a carbocyclic or heterocyclic group selected from thegroup consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,phenyl, oxirane, oxetane, thiirane, thietane, aziridine, azetidine,pyrrolidine, pyrrole, thiophene, oxazole, isoxazole, isoxazoline,thiazole, isothiazole, 1,3,4-thiadazole, pyrazole, imidazole, triazole,tetrazole, furan, tetrahydrofuran and dihydrofuran, wherein saidcarbocyclic or heterocyclic groups may be further substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino, and theothers of R¹ to R⁴ are independently G-1 wherein R^(1A), R^(1B), R^(1C),R^(1D) and R^(1E) are independently hydrogen, halogen, C₁-C₃-alkyl orC₁-C₃-haloalkyl.

In another embodiment, one, two or three of R¹ to R⁴ are independentlycyclopropyl or methylene (—CH₂—) or methylene substituted by one or twohalogen atoms (—CHX— or —CX₂— where X is halogen) which are substitutedby a carbocyclic or heterocyclic group selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,phenyl, oxetane, pyrrole, tetrahydrofuran and dihydrofuran, wherein saidcarbocyclic or heterocyclic groups may be further substituted by one ormore substituents selected from the group consisting of halogen,hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl, heterocyclyl, phenyl,heteroaryl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino, and theothers of R¹ to R⁴ are independently G-1 wherein R^(1A), R^(1B), R^(1C),R^(1D) and R^(1E) are independently hydrogen, fluorine, C₁-C₃-alkyl orC₁-C₃-haloalkyl.

In yet another embodiment, one, two or three of R¹ to R⁴ are cyclopropylor methylene (—CH₂—) or methylene substituted by one or two halogenatoms (—CHX— or —CX₂— where X is halogen) which are substituted by acarbocyclic or heterocyclic group selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl phenyl and oxetane,wherein said carbocyclic or heterocyclic groups may be furthersubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkyl, haloalkyl, C₃-C₆cycloalkyl,heterocyclyl, phenyl, heteroaryl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylaminoand dialkylamino, and the others of R¹ to R⁴ are independently G-1wherein R^(1A), R^(1B), R^(1C), R^(1D) and R^(1E) are independentlyhydrogen, fluorine, C₁-C₃-alkyl or C₁-C₃-haloalkyl.

In yet another embodiment, one, two or three of R¹ to R⁴ are cyclopropylor methylene (—CH₂—) or methylene substituted by one or two halogenatoms (—CHX— or —CX₂— where X is halogen) which are substituted by acyclopropyl optionally substituted by halogen, and the others of R¹ toR⁴ are independently G-1 wherein R^(1A), R^(1B), R^(1C), R^(1D) andR^(1E) are independently hydrogen, fluorine, methyl or trifluoromethyl.

In one embodiment, one, two or three of R¹ to R⁴ are cyclopropyl ormethylene (—CH₂—) or methylene substituted by one or two halogen atoms(—CHX— or —CX₂— where X is halogen) which are substituted by acyclopropyl optionally substituted by halogen, and the others of R¹ toR⁴ are independently G-1 wherein R^(1A), R^(1B), R^(1C), R^(1D) andR^(1E) are independently hydrogen, fluoro, C₁-C₃ alkyl or C₁-C₃haloalkyl.

In yet another embodiment, one, two or three of R¹ to R⁴ are cyclopropylor methylene (—CH₂—) or methylene substituted by one or two halogenatoms (—CHX— or —CX₂— where X is halogen) which are substituted by acyclopropyl optionally substituted by halogen, and the others of R¹ toR⁴ are independently G-1 wherein R^(1D) and R^(1E) are independently Hor halogen. In another embodiment, R^(1D) and R^(1E) are independentlyC₁-C₃ alkyl or C₁-C₃ haloalkyl. In another embodiment, R^(1A) is H orhalogen. In another embodiment, R^(1A) is C₁-C₃ alkyl or C₁-C₃haloalkyl. In another embodiment, R^(1A) is halogen, and R^(1B) andR^(1C) are independently C₁-C₃ alkyl or C₁-C₃ haloalkyl. In yet anotherembodiment, R^(1D) and R^(1E) are H, R^(1A) is halogen, and R^(1B) andR^(1C) are independently C₁-C₃ alkyl or C₁-C₃ haloalkyl.

In yet another embodiment, one, two or three of R¹ to R⁴ are cyclopropylor methylene (—CH₂—) or methylene substituted by one or two halogenatoms (—CHX— or —CX₂— where X is halogen) which are substituted by acyclopropyl optionally substituted by halogen, and the others of R¹ toR⁴ are independently G-1 wherein R^(1D) and R^(1E) are independently Hor F. In another embodiment, R^(1D) and R^(1E) are independently methylor trifluoromethyl. In another embodiment, R^(1A) is H or F. In anotherembodiment, R^(1A) is methyl or trifluoromethyl. In another embodiment,R^(1A) is F, and R^(1B) and R^(1C) are methyl or trifluoromethyl. In yetanother embodiment, R^(1D) and R^(1E) are H, R^(1A) is F, R^(1B) andR^(1C) are methyl or trifluoromethyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C1 to C28 shown below:

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C1 to C8. In another embodiment, one, two, three or allfour of R¹ to R⁴ are independently C9 to C15. In yet another embodiment,one, two, three or all four of R¹ to R⁴ are independently C16 to C20. Inanother embodiment, one, two, three or all four of R¹ to R⁴ areindependently C21 to C26. In another embodiment, one, two, three or allfour of R¹ to R⁴ together with the corresponding R^(1′) to R^(4′) areC27 or C28. In another embodiment, one, two, three or all four of R¹ toR⁴, are independently C1 to C26 and the other of R¹ to R⁴ areindependently C₁-C₆ alkyl, optionally substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkyl sulfinyl, haloalkylsulfinyl, alkyl sulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino.

In yet another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C1 to C26 and the other of R¹ to R⁴ are independentlyC₁-C₃ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino. In another embodiment, one,two, three or all four of R¹ to R⁴ are independently C1 to C26 and theother of R¹ to R⁴ are independently 2-methylpropyl or2,2-dimethylpropyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ togetherwith the corresponding R^(1′) to R^(4′) are C27 or C28 and the other ofR¹ to R⁴ and the corresponding R^(1′) to R^(4′) are independentlyhydrogen or C₁-C₃ alkyl, optionally substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino. In anotherembodiment, one, two, three or all four of R¹ to R⁴ and thecorresponding R^(1′) to R^(4′) are independently C27 or C28 and theother of R¹ to R⁴ and the corresponding R^(1′) to R^(4′) areindependently hydrogen, 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C1 to C26 and the other of R¹ to R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.

In another embodiment, one, two, three or all four of R¹ to R⁴ and thecorresponding R^(1′) to R^(4′) are independently C27 or C28 and theother of R¹ to R⁴ and the corresponding R^(1′) to R^(4′) areindependently hydrogen or 2,2-dimethylpropyl or 2-methylpropylsubstituted by one or more substituents selected from the groupconsisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino.

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C1 to C26 and the other of R¹ to R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or more halogen.

In another embodiment, one, two, three or all four of R¹ to R⁴ and thecorresponding R^(1′) to R^(4′) are independently C27 or C28 and theother of R¹ to R⁴ and the corresponding R^(1′) to R^(4′) areindependently hydrogen or 2,2-dimethylpropyl or 2-methylpropylsubstituted by one or more halogen.

In still another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C1 to C26 and the other of R¹ to R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or morefluorine.

In another embodiment, one, two, three or all four of R¹ to R⁴ and thecorresponding R^(1′) to R^(4′) are independently C27 or C28 and theother of R¹ to R⁴ and the corresponding R^(1′) to R^(4′) areindependently hydrogen or 2,2-dimethylpropyl or 2-methylpropyl,substituted by one or more fluorine.

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C1 to C26 and the other of R¹ to R⁴ are independently thegroup G-1 wherein R^(1A), R^(1B), R^(1C), R^(1D) and R^(1E) areindependently hydrogen, halogen, alkyl or haloalkyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C1 or C2 and the other of R¹ to R⁴ are independently2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C3, C4 or C5 and the other of R¹ to R⁴ are independently2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In still another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C6, C7 or C8 and the other of R¹ to R⁴ are independently2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C9, C10 or C11 and the other of R¹ to R⁴ are independently2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In yet another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C12, C13, C14 or C15 and the other of R¹ to R⁴ areindependently 2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ areindependently C16 to C20 and the other of R¹ to R⁴ are independently2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl. In yet another embodiment, R¹ and R³ areindependently C1 to C26 and R² and R⁴ are independently 2-methylpropylsubstituted by one or more fluorine or 2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are independently C1 or C2 and R² andR⁴ are independently 2-methylpropyl substituted by one or more fluorineor 2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are independently C3, C4, C5 or C6 andR² and R⁴ are independently 2-methylpropyl substituted by one or morefluorine or 2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are independently C7 or C8 and R² andR⁴ are independently 2-methylpropyl substituted by one or more fluorineor 2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are independently C9, C10 or C11 and R²and R⁴ are independently 2-methylpropyl substituted by one or morefluorine or 2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are independently C12, C13, C14 or C15and R² and R⁴ are independently 2-methylpropyl substituted by one ormore fluorine or 2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are independently C16, C17, C18, C19 orC20 and R² and R⁴ are independently 2-methylpropyl substituted by one ormore fluorine or 2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are independently C21, C22, C23, C24,C25 or C26 and R² and R⁴ are independently 2-methylpropyl substituted byone or more fluorine or 2,2-dimethylpropyl.

In another embodiment, R¹ together with R^(1′) and/or R³ together withR^(3′) form a 2- to 3-membered carbon chain to form a cyclopropyl orcyclobutyl ring and R², R^(2′), R⁴ and R^(4′) are independentlyhydrogen, 2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In yet another embodiment, R² and R⁴ are independently C1 to C26 and R¹and R³ are independently 2-methylpropyl substituted by one or morefluorine or 2,2-dimethylpropyl.

In another embodiment, R² and R⁴ are independently C1 or C2 and R¹ andR³ are independently 2-methylpropyl substituted by one or more fluorineor 2,2-dimethylpropyl.

In another embodiment, R² and R⁴ are independently C3, C4, C5 or C6 andR¹ and R³ are independently 2-methylpropyl substituted by one or morefluorine or 2,2-dimethylpropyl.

In another embodiment, R² and R⁴ are independently C7 or C8 and R¹ andR³ are independently 2-methylpropyl substituted by one or more fluorineor 2,2-dimethylpropyl.

In another embodiment, R² and R⁴ are independently C9, C10 or C11 and R¹and R³ are independently 2-methylpropyl substituted by one or morefluorine or 2,2-dimethylpropyl.

In another embodiment, R² and R⁴ are independently C12, C13, C14 or C15and R¹ and R³ are independently 2-methylpropyl substituted by one ormore fluorine or 2,2-dimethylpropyl.

In another embodiment, R² and R⁴ are independently C16, C17, C18, C19 orC20 and R¹ and R³ are independently 2-methylpropyl substituted by one ormore fluorine or 2,2-dimethylpropyl.

In another embodiment, R² and R⁴ are independently C21, C22, C23, C24,C25 or C26 and R¹ and R³ are independently 2-methylpropyl substituted byone or more fluorine or 2,2-dimethylpropyl.

In another embodiment, R² together with R^(2′) and/or R⁴ together withR^(4∝) form a 2- to 3-membered carbon chain to form a cyclopropyl orcyclobutyl ring and R¹, R^(1′), R³ and R^(3′) are independentlyhydrogen, 2-methylpropyl substituted by one or more fluorine or2,2-dimethylpropyl.

In one embodiment, the invention provides compounds of formula (I)wherein R′, R″, R′″ and R″″ are each independently hydrogen orC₁-C₃alkyl; and Cy¹, Cy², and R^(a), R^(b), R¹, R², R³ and R⁴ are asdescribed in Tables 2 to 38 below. In the compounds described in Tables2 to 38, the variables R^(1′), R^(2′), R^(3′) and R^(4′) are hydrogenunless they form a carbon chain with the corresponding R¹ to R⁴ to forma ring (e.g. when forming C27 or C28).

Compounds in Tables 2 to 38 where all of R^(a), R^(b), R′, R″, R′″ andR″″ are methyl are designated by the compound number X-YA, where X isthe table number and Y is the sequential number in the table. Compoundsin Tables 2 to 38 wherein R^(a), R^(b) are each hydrogen and R′, R″, R′″and R″″ are methyl are designated by the compound number X-YB. Compoundsin Tables 2 to 38 wherein R^(a), R^(b) are each methyl and R′, R″, R′″and R″″ are hydrogen are designated by the compound numbers X-YC; andCompounds in Tables 2 to 38 wherein R^(a), R^(b) are each hydrogen andR′, R″, R′″ and R″″ are methyl are designated by the compound numbersX-YD.

TABLE 2 Compounds of formula (I), wherein Cy¹ and Cy² are unsubstitutedphenyl, R′, R″, R′″ and R″″ are each independently hydrogen or methyl,and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd # R^(a)/R^(b) R¹ R² R³R⁴ 2-1 CH₃ Cl Cl Cl Cl 2-2 CH₃ Cl —CH₂—iPr —CH₂—iPr —CH₂—iPr 2-3 CH₃—CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 2-4 CH₃ —CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 2-5CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 2-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 2-7CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 2-8 CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 2-9 CH₃ ClCl —CH₂—iPr —CH₂—iPr 2-10 CH₃ —CH₂—iPr —CH₂—iPr Cl Cl 2-11 CH₃ Cl—CH₂—iPr —CH₂—iPr Cl 2-12 CH₃ —CH₂—iPr Cl Cl Cl 2-13 CH₃ Cl —CH₂—iPr ClCl 2-14 CH₃ Cl Cl —CH₂—iPr Cl 2-15 CH₃ Cl Cl Cl —CH₂—iPr 2-16 CH₃ Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 2-17 CH₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 2-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ 2-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 2-20 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 2-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃2-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 2-23 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 2-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 2-25 CH₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 2-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 2-27 CH₃Cl —CH₂—C(CH₃)₃ Cl Cl 2-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 2-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 2-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 2-31 CH₃—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 2-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 2-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 2-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 2-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 2-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂2-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 2-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 2-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 2-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 2-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 2-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 2-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 2-44 CH₃ Cl n-Propyln-Propyl n-Propyl 2-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 2-46 CH₃n-Propyl n-Propyl Cl n-Propyl 2-47 CH₃ n-Propyl n-Propyl n-Propyl Cl2-48 CH₃ n-Propyl Cl n-Propyl Cl 2-49 CH₃ Cl n-Propyl Cl n-Propyl 2-50CH₃ n-Propyl Cl Cl n-Propyl 2-51 CH₃ Cl Cl n-Propyl n-Propyl 2-52 CH₃n-Propyl n-Propyl Cl Cl 2-53 CH₃ Cl n-Propyl n-Propyl Cl 2-54 CH₃n-Propyl Cl Cl Cl 2-55 CH₃ Cl n-Propyl Cl Cl 2-56 CH₃ Cl Cl n-Propyl Cl2-57 CH₃ Cl Cl Cl n-Propyl 2-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 2-59 HCl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 2-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂2-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 2-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 2-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 2-64 H —CH₂—C(CH₃)₃Cl —CH₂—C(CH₃)₃ Cl 2-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 2-66 H—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 2-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl2-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 2-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl Cl

TABLE 3 Compounds of formula (I), wherein Cy¹ and Cy² arep-fluorophenyl; R′, R″, R′″ and R″″ are each independently hydrogen ormethyl; and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd # R^(a)/R^(b)R¹ R² R³ R⁴ 3-1 CH₃ Cl Cl Cl Cl 3-2 CH₃ Cl —CH₂—iPr —CH₂—iPr —CH₂—iPr3-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 3-4 CH₃ —CH₂—iPr —CH₂—iPr Cl—CH₂—iPr 3-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 3-6 CH₃ —CH₂—iPr Cl—CH₂—iPr Cl 3-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 3-8 CH₃ —CH₂—iPr Cl Cl—CH₂—iPr 3-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 3-10 CH₃ —CH₂—iPr —CH₂—iPr ClCl 3-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 3-12 CH₃ —CH₂—iPr Cl Cl Cl 3-13 CH₃Cl —CH₂—iPr Cl Cl 3-14 CH₃ Cl Cl —CH₂—iPr Cl 3-15 CH₃ Cl Cl Cl —CH₂—iPr3-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 3-17 CH₃ —CH₂—C(CH₃)₃Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 3-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ 3-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 3-20 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 3-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃3-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 3-23 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 3-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 3-25 CH₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 3-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 3-27 CH₃Cl —CH₂—C(CH₃)₃ Cl Cl 3-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 3-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 3-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 3-31 CH₃—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 3-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 3-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 3-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 3-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 3-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂3-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 3-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 3-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 3-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 3-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 3-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 3-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 3-44 CH₃ Cl n-Propyln-Propyl n-Propyl 3-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 3-46 CH₃n-Propyl n-Propyl Cl n-Propyl 3-47 CH₃ n-Propyl n-Propyl n-Propyl Cl3-48 CH₃ n-Propyl Cl n-Propyl Cl 3-49 CH₃ Cl n-Propyl Cl n-Propyl 3-50CH₃ n-Propyl Cl Cl n-Propyl 3-51 CH₃ Cl Cl n-Propyl n-Propyl 3-52 CH₃n-Propyl n-Propyl Cl Cl 3-53 CH₃ Cl n-Propyl n-Propyl Cl 3-54 CH₃n-Propyl Cl Cl Cl 3-55 CH₃ Cl n-Propyl Cl Cl 3-56 CH₃ Cl Cl n-Propyl Cl3-57 CH₃ Cl Cl Cl n-Propyl 3-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 3-59 HCl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 3-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂3-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 3-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 3-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 3-64 H —CH₂—C(CH₃)₃Cl —CH₂—C(CH₃)₃ Cl 3-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 3-66 H—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 3-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl3-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 3-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl Cl

TABLE 4 Compounds of formula (I), wherein Cy¹ and Cy² arep-trifluoromethylphenyl; R′, R″, R′″ and R″″ are each independentlyhydrogen or methyl; and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd #R^(a)/R^(b) R¹ R² R³ R⁴ 4-1 CH₃ Cl Cl Cl Cl 4-2 CH₃ Cl —CH₂—iPr —CH₂—iPr—CH₂—iPr 4-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 4-4 CH₃ —CH₂—iPr —CH₂—iPrCl —CH₂—iPr 4-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 4-6 CH₃ —CH₂—iPr Cl—CH₂—iPr Cl 4-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 4-8 CH₃ —CH₂—iPr Cl Cl—CH₂—iPr 4-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 4-10 CH₃ —CH₂—iPr —CH₂—iPr ClCl 4-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 4-12 CH₃ —CH₂—iPr Cl Cl Cl 4-13 CH₃Cl —CH₂—iPr Cl Cl 4-14 CH₃ Cl Cl —CH₂—iPr Cl 4-15 CH₃ Cl Cl Cl —CH₂—iPr4-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 4-17 CH₃ —CH₂—C(CH₃)₃Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 4-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ 4-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 4-20 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 4-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃4-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 4-23 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 4-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 4-25 CH₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 4-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 4-27 CH₃Cl —CH₂—C(CH₃)₃ Cl Cl 4-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 4-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 4-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 4-31 CH₃—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 4-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 4-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 4-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 4-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 4-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂4-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 4-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 4-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 4-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 4-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 4-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 4-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 4-44 CH₃ Cl n-Propyln-Propyl n-Propyl 4-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 4-46 CH₃n-Propyl n-Propyl Cl n-Propyl 4-47 CH₃ n-Propyl n-Propyl n-Propyl Cl4-48 CH₃ n-Propyl Cl n-Propyl Cl 4-49 CH₃ Cl n-Propyl Cl n-Propyl 4-50CH₃ n-Propyl Cl Cl n-Propyl 4-51 CH₃ Cl Cl n-Propyl n-Propyl 4-52 CH₃n-Propyl n-Propyl Cl Cl 4-53 CH₃ Cl n-Propyl n-Propyl Cl 4-54 CH₃n-Propyl Cl Cl Cl 4-55 CH₃ Cl n-Propyl Cl Cl 4-56 CH₃ Cl Cl n-Propyl Cl4-57 CH₃ Cl Cl Cl n-Propyl 4-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 4-59 HCl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 4-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂4-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 4-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 4-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 4-64 H —CH₂—C(CH₃)₃Cl —CH₂—C(CH₃)₃ Cl 4-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 4-66 H—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 4-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl4-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 4-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl Cl

TABLE 5 Compounds of formula (I), wherein Cy¹ and Cy² arep-trifluoromethoxyphenyl; R′, R″, R′″ and R″″ are each independentlyhydrogen or methyl; and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd #R^(a)/R^(b) R¹ R² R³ R⁴ 5-1 CH₃ Cl Cl Cl Cl 5-2 CH₃ Cl —CH₂—iPr —CH₂—iPr—CH₂—iPr 5-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 5-4 CH₃ —CH₂—iPr —CH₂—iPrCl —CH₂—iPr 5-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 5-6 CH₃ —CH₂—iPr Cl—CH₂—iPr Cl 5-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 5-8 CH₃ —CH₂—iPr Cl Cl—CH₂—iPr 5-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 5-10 CH₃ —CH₂—iPr —CH₂—iPr ClCl 5-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 5-12 CH₃ —CH₂—iPr Cl Cl Cl 5-13 CH₃Cl —CH₂—iPr Cl Cl 5-14 CH₃ Cl Cl —CH₂—iPr Cl 5-15 CH₃ Cl Cl Cl —CH₂—iPr5-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 5-17 CH₃ —CH₂—C(CH₃)₃Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 5-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ 5-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 5-20 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 5-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃5-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 5-23 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 5-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 5-25 CH₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 5-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 5-27 CH₃Cl —CH₂—C(CH₃)₃ Cl Cl 5-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 5-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 5-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 5-31 CH₃—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 5-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 5-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 5-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 5-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 5-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂5-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 5-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 5-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 5-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 5-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 5-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 5-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 5-44 CH₃ Cl n-Propyln-Propyl n-Propyl 5-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 5-46 CH₃n-Propyl n-Propyl Cl n-Propyl 5-47 CH₃ n-Propyl n-Propyl n-Propyl Cl5-48 CH₃ n-Propyl Cl n-Propyl Cl 5-49 CH₃ Cl n-Propyl Cl n-Propyl 5-50CH₃ n-Propyl Cl Cl n-Propyl 5-51 CH₃ Cl Cl n-Propyl n-Propyl 5-52 CH₃n-Propyl n-Propyl Cl Cl 5-53 CH₃ Cl n-Propyl n-Propyl Cl 5-54 CH₃n-Propyl Cl Cl Cl 5-55 CH₃ Cl n-Propyl Cl Cl 5-56 CH₃ Cl Cl n-Propyl Cl5-57 CH₃ Cl Cl Cl n-Propyl 5-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 5-59 HCl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 5-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂5-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 5-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 5-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 5-64 H —CH₂—C(CH₃)₃Cl —CH₂—C(CH₃)₃ Cl 5-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 5-66 H—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 5-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl5-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 5-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl Cl

TABLE 6

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 6-1 CH₃ Cl Cl Cl Cl 6-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 6-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 6-4 CH₃ —CH₂—iPr—CH₂—iPr Cl —CH₂—iPr 6-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 6-6 CH₃—CH₂—iPr Cl —CH₂—iPr Cl 6-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 6-8 CH₃ —CH₂—iPrCl Cl —CH₂—iPr 6-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 6-10 CH₃ —CH₂—iPr—CH₂—iPr Cl Cl 6-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 6-12 CH₃ —CH₂—iPr Cl ClCl 6-13 CH₃ Cl —CH₂—iPr Cl Cl 6-14 CH₃ Cl Cl —CH₂—iPr Cl 6-15 CH₃ Cl ClCl —CH₂—iPr 6-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 6-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 6-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 6-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 6-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 6-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 6-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃6-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 6-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 6-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 6-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 6-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 6-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 6-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 6-30 CH₃ Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 6-31 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 6-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 6-33 CH₃—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 6-34 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 6-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 6-36 CH₃—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 6-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl6-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 6-39 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 6-40 CH₃ —CH₂CF(CH₃)₂ Cl Cl Cl 6-41 CH₃ Cl—CH₂CF(CH₃)₂ Cl Cl 6-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 6-43 CH₃ Cl Cl Cl—CH₂CF(CH₃)₂ 6-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 6-45 CH₃ n-Propyl Cln-Propyl n-Propyl 6-46 CH₃ n-Propyl n-Propyl Cl n-Propyl 6-47 CH₃n-Propyl n-Propyl n-Propyl Cl 6-48 CH₃ n-Propyl Cl n-Propyl Cl 6-49 CH₃Cl n-Propyl Cl n-Propyl 6-50 CH₃ n-Propyl Cl Cl n-Propyl 6-51 CH₃ Cl Cln-Propyl n-Propyl 6-52 CH₃ n-Propyl n-Propyl Cl Cl 6-53 CH₃ Cl n-Propyln-Propyl Cl 6-54 CH₃ n-Propyl Cl Cl Cl 6-55 CH₃ Cl n-Propyl Cl Cl 6-56CH₃ Cl Cl n-Propyl Cl 6-57 CH₃ Cl Cl Cl n-Propyl 6-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 6-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 6-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 6-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl6-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 6-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂Cl Cl 6-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 6-65 H Cl —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ 6-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 6-67 H Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 6-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 6-69H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 7

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 7-1 CH₃ Cl Cl Cl Cl 7-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 7-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 7-4 CH₃ —CH₂—iPr—CH₂—iPr Cl —CH₂—iPr 7-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 7-6 CH₃—CH₂—iPr Cl —CH₂—iPr Cl 7-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 7-8 CH₃ —CH₂—iPrCl Cl —CH₂—iPr 7-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 7-10 CH₃ —CH₂—iPr—CH₂—iPr Cl Cl 7-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 7-12 CH₃ —CH₂—iPr Cl ClCl 7-13 CH₃ Cl —CH₂—iPr Cl Cl 7-14 CH₃ Cl Cl —CH₂—iPr Cl 7-15 CH₃ Cl ClCl —CH₂—iPr 7-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 7-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 7-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 7-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 7-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 7-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 7-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃7-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 7-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 7-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 7-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 7-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 7-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 7-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 7-30 CH₃ Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 7-31 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 7-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 7-33 CH₃—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 7-34 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 7-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 7-36 CH₃—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 7-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl7-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 7-39 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 7-40 CH₃ —CH₂CF(CH₃)₂ Cl Cl Cl 7-41 CH₃ Cl—CH₂CF(CH₃)₂ Cl Cl 7-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 7-43 CH₃ Cl Cl Cl—CH₂CF(CH₃)₂ 7-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 7-45 CH₃ n-Propyl Cln-Propyl n-Propyl 7-46 CH₃ n-Propyl n-Propyl Cl n-Propyl 7-47 CH₃n-Propyl n-Propyl n-Propyl Cl 7-48 CH₃ n-Propyl Cl n-Propyl Cl 7-49 CH₃Cl n-Propyl Cl n-Propyl 7-50 CH₃ n-Propyl Cl Cl n-Propyl 7-51 CH₃ Cl Cln-Propyl n-Propyl 7-52 CH₃ n-Propyl n-Propyl Cl Cl 7-53 CH₃ Cl n-Propyln-Propyl Cl 7-54 CH₃ n-Propyl Cl Cl Cl 7-55 CH₃ Cl n-Propyl Cl Cl 7-56CH₃ Cl Cl n-Propyl Cl 7-57 CH₃ Cl Cl Cl n-Propyl 7-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 7-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 7-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 7-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl7-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 7-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂Cl Cl 7-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 7-65 H Cl —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ 7-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 7-67 H Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 7-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 7-69H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 8

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 8-1 CH₃ Cl Cl Cl Cl 8-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 8-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 8-4 CH₃ —CH₂—iPr—CH₂—iPr Cl —CH₂—iPr 8-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 8-6 CH₃—CH₂—iPr Cl —CH₂—iPr Cl 8-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 8-8 CH₃ —CH₂—iPrCl Cl —CH₂—iPr 8-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 8-10 CH₃ —CH₂—iPr—CH₂—iPr Cl Cl 8-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 8-12 CH₃ —CH₂—iPr Cl ClCl 8-13 CH₃ Cl —CH₂—iPr Cl Cl 8-14 CH₃ Cl Cl —CH₂—iPr Cl 8-15 CH₃ Cl ClCl —CH₂—iPr 8-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 8-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 8-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 8-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 8-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 8-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 8-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃8-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 8-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 8-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 8-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 8-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 8-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 8-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 8-30 CH₃ Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 8-31 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 8-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 8-33 CH₃—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 8-34 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 8-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 8-36 CH₃—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 8-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl8-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 8-39 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 8-40 CH₃ —CH₂CF(CH₃)₂ Cl Cl Cl 8-41 CH₃ Cl—CH₂CF(CH₃)₂ Cl Cl 8-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 8-43 CH₃ Cl Cl Cl—CH₂CF(CH₃)₂ 8-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 8-45 CH₃ n-Propyl Cln-Propyl n-Propyl 8-46 CH₃ n-Propyl n-Propyl Cl n-Propyl 8-47 CH₃n-Propyl n-Propyl n-Propyl Cl 8-48 CH₃ n-Propyl Cl n-Propyl Cl 8-49 CH₃Cl n-Propyl Cl n-Propyl 8-50 CH₃ n-Propyl Cl Cl n-Propyl 8-51 CH₃ Cl Cln-Propyl n-Propyl 8-52 CH₃ n-Propyl n-Propyl Cl Cl 8-53 CH₃ Cl n-Propyln-Propyl Cl 8-54 CH₃ n-Propyl Cl Cl Cl 8-55 CH₃ Cl n-Propyl Cl Cl 8-56CH₃ Cl Cl n-Propyl Cl 8-57 CH₃ Cl Cl Cl n-Propyl 8-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 8-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 8-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 8-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl8-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 8-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂Cl Cl 8-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 8-65 H Cl —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ 8-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 8-67 H Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 8-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 8-69H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 9

Cmpd # R^(a)/R^(b) R1 R² R³ R⁴ 9-1 CH₃ Cl Cl Cl Cl 9-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 9-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 9-4 CH₃ —CH₂—iPr—CH₂—iPr Cl —CH₂—iPr 9-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 9-6 CH₃—CH₂—iPr Cl —CH₂—iPr Cl 9-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 9-8 CH₃ —CH₂—iPrCl Cl —CH₂—iPr 9-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 9-10 CH₃ —CH₂—iPr—CH₂—iPr Cl Cl 9-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 9-12 CH₃ —CH₂—iPr Cl ClCl 9-13 CH₃ Cl —CH₂—iPr Cl Cl 9-14 CH₃ Cl Cl —CH₂—iPr Cl 9-15 CH₃ Cl ClCl —CH₂—iPr 9-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 9-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 9-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 9-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 9-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 9-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 9-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃9-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 9-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 9-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 9-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 9-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 9-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 9-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 9-30 CH₃ Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 9-31 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 9-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 9-33 CH₃—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 9-34 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 9-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 9-36 CH₃—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 9-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl9-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 9-39 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 9-40 CH₃ —CH₂CF(CH₃)₂ Cl Cl Cl 9-41 CH₃ Cl—CH₂CF(CH₃)₂ Cl Cl 9-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 9-43 CH₃ Cl Cl Cl—CH₂CF(CH₃)₂ 9-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 9-45 CH₃ n-Propyl Cln-Propyl n-Propyl 9-46 CH₃ n-Propyl n-Propyl Cl n-Propyl 9-47 CH₃n-Propyl n-Propyl n-Propyl Cl 9-48 CH₃ n-Propyl Cl n-Propyl Cl 9-49 CH₃Cl n-Propyl Cl n-Propyl 9-50 CH₃ n-Propyl Cl Cl n-Propyl 9-51 CH₃ Cl Cln-Propyl n-Propyl 9-52 CH₃ n-Propyl n-Propyl Cl Cl 9-53 CH₃ Cl n-Propyln-Propyl Cl 9-54 CH₃ n-Propyl Cl Cl Cl 9-55 CH₃ Cl n-Propyl Cl Cl 9-56CH₃ Cl Cl n-Propyl Cl 9-57 CH₃ Cl Cl Cl n-Propyl 9-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 9-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 9-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 9-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl9-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 9-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂Cl Cl 9-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 9-65 H Cl —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ 9-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 9-67 H Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 9-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 9-69H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 10

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 10-1 CH₃ Cl Cl Cl Cl 10-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 10-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 10-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 10-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl10-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 10-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 10-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 10-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 10-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 10-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 10-12 CH₃—CH₂—iPr Cl Cl Cl 10-13 CH₃ Cl —CH₂—iPr Cl Cl 10-14 CH₃ Cl Cl —CH₂—iPrCl 10-15 CH₃ Cl Cl Cl —CH₂—iPr 10-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 10-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 10-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 10-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 10-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl10-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 10-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 10-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 10-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 10-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl10-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 10-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 10-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 10-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 10-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 10-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 10-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 10-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 10-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 10-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 10-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 10-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 10-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂10-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 10-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 10-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 10-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 10-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 10-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 10-45CH₃ n-Propyl Cl n-Propyl n-Propyl 10-46 CH₃ n-Propyl n-Propyl Cln-Propyl 10-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 10-48 CH₃ n-Propyl Cln-Propyl Cl 10-49 CH₃ Cl n-Propyl Cl n-Propyl 10-50 CH₃ n-Propyl Cl Cln-Propyl 10-51 CH₃ Cl Cl n-Propyl n-Propyl 10-52 CH₃ n-Propyl n-PropylCl Cl 10-53 CH₃ Cl n-Propyl n-Propyl Cl 10-54 CH₃ n-Propyl Cl Cl Cl10-55 CH₃ Cl n-Propyl Cl Cl 10-56 CH₃ Cl Cl n-Propyl Cl 10-57 CH₃ Cl ClCl n-Propyl 10-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 10-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 10-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂10-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 10-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 10-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 10-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 10-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃10-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 10-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 10-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 10-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 11

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 11-1 CH₃ Cl Cl Cl Cl 11-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 11-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 11-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 11-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl11-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 11-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 11-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 11-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 11-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 11-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 11-12 CH₃—CH₂—iPr Cl Cl Cl 11-13 CH₃ Cl —CH₂—iPr Cl Cl 11-14 CH₃ Cl Cl —CH₂—iPrCl 11-15 CH₃ Cl Cl Cl —CH₂—iPr 11-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 11-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 11-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 11-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 11-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl11-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 11-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 11-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 11-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 11-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl11-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 11-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 11-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 11-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 11-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 11-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 11-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 11-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 11-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 11-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 11-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 11-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 11-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂11-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 11-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 11-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 11-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 11-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 11-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 11-45CH₃ n-Propyl Cl n-Propyl n-Propyl 11-46 CH₃ n-Propyl n-Propyl Cln-Propyl 11-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 11-48 CH₃ n-Propyl Cln-Propyl Cl 11-49 CH₃ Cl n-Propyl Cl n-Propyl 11-50 CH₃ n-Propyl Cl Cln-Propyl 11-51 CH₃ Cl Cl n-Propyl n-Propyl 11-52 CH₃ n-Propyl n-PropylCl Cl 11-53 CH₃ Cl n-Propyl n-Propyl Cl 11-54 CH₃ n-Propyl Cl Cl Cl11-55 CH₃ Cl n-Propyl Cl Cl 11-56 CH₃ Cl Cl n-Propyl Cl 11-57 CH₃ Cl ClCl n-Propyl 11-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 11-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 11-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂11-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 11-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 11-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 11-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 11-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃11-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 11-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 11-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 11-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 12

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 12-1 CH₃ Cl Cl Cl Cl 12-2 CH₃ Cl —CH₂-iPr—CH₂-iPr —CH₂-iPr 12-3 CH₃ —CH₂-iPr Cl —CH₂-iPr —CH₂-iPr 12-4 CH₃—CH₂-iPr —CH₂-iPr Cl —CH₂-iPr 12-5 CH₃ —CH₂-iPr —CH₂-iPr —CH₂-iPr Cl12-6 CH₃ —CH₂-iPr Cl —CH₂-iPr Cl 12-7 CH₃ Cl —CH₂-iPr Cl —CH₂-iPr 12-8CH₃ —CH₂-iPr Cl Cl —CH₂-iPr 12-9 CH₃ Cl Cl —CH₂-iPr —CH₂-iPr 12-10 CH₃—CH₂-iPr —CH₂-iPr Cl Cl 12-11 CH₃ Cl —CH₂-iPr —CH₂-iPr Cl 12-12 CH₃—CH₂-iPr Cl Cl Cl 12-13 CH₃ Cl —CH₂-iPr Cl Cl 12-14 CH₃ Cl Cl —CH₂-iPrCl 12-15 CH₃ Cl Cl Cl —CH₂-iPr 12-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 12-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 12-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 12-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 12-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl12-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 12-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 12-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 12-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 12-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl12-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 12-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 12-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 12-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 12-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 12-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 12-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 12-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 12-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 12-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 12-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 12-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 12-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂12-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 12-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 12-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 12-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 12-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 12-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 12-45CH₃ n-Propyl Cl n-Propyl n-Propyl 12-46 CH₃ n-Propyl n-Propyl Cln-Propyl 12-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 12-48 CH₃ n-Propyl Cln-Propyl Cl 12-49 CH₃ Cl n-Propyl Cl n-Propyl 12-50 CH₃ n-Propyl Cl Cln-Propyl 12-51 CH₃ Cl Cl n-Propyl n-Propyl 12-52 CH₃ n-Propyl n-PropylCl Cl 12-53 CH₃ Cl n-Propyl n-Propyl Cl 12-54 CH₃ n-Propyl Cl Cl Cl12-55 CH₃ Cl n-Propyl Cl Cl 12-56 CH₃ Cl Cl n-Propyl Cl 12-57 CH₃ Cl ClCl n-Propyl 12-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 12-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 12-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂12-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 12-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 12-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 12-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 12-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃12-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 12-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 12-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 12-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 13

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 13-1 CH₃ Cl Cl Cl Cl 13-2 CH₃ Cl —CH₂-iPr—CH₂-iPr —CH₂-iPr 13-3 CH₃ —CH₂-iPr Cl —CH₂-iPr —CH₂-iPr 13-4 CH₃—CH₂-iPr —CH₂-iPr Cl —CH₂-iPr 13-5 CH₃ —CH₂-iPr —CH₂-iPr —CH₂-iPr Cl13-6 CH₃ —CH₂-iPr Cl —CH₂-iPr Cl 13-7 CH₃ Cl —CH₂-iPr Cl —CH₂-iPr 13-8CH₃ —CH₂-iPr Cl Cl —CH₂-iPr 13-9 CH₃ Cl Cl —CH₂-iPr —CH₂-iPr 13-10 CH₃—CH₂-iPr —CH₂-iPr Cl Cl 13-11 CH₃ Cl —CH₂-iPr —CH₂-iPr Cl 13-12 CH₃—CH₂-iPr Cl Cl Cl 13-13 CH₃ Cl —CH₂-iPr Cl Cl 13-14 CH₃ Cl Cl —CH₂-iPrCl 13-15 CH₃ Cl Cl Cl —CH₂-iPr 13-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 13-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 13-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 13-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 13-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl13-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 13-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 13-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 13-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 13-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl13-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 13-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 13-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 13-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 13-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 13-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 13-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 13-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 13-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 13-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 13-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 13-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 13-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂13-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 13-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 13-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 13-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 13-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 13-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 13-45CH₃ n-Propyl Cl n-Propyl n-Propyl 13-46 CH₃ n-Propyl n-Propyl Cln-Propyl 13-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 13-48 CH₃ n-Propyl Cln-Propyl Cl 13-49 CH₃ Cl n-Propyl Cl n-Propyl 13-50 CH₃ n-Propyl Cl Cln-Propyl 13-51 CH₃ Cl Cl n-Propyl n-Propyl 13-52 CH₃ n-Propyl n-PropylCl Cl 13-53 CH₃ Cl n-Propyl n-Propyl Cl 13-54 CH₃ n-Propyl Cl Cl Cl13-55 CH₃ Cl n-Propyl Cl Cl 13-56 CH₃ Cl Cl n-Propyl Cl 13-57 CH₃ Cl ClCl n-Propyl 13-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 13-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 13-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂13-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 13-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 13-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 13-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 13-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃13-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 13-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 13-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 13-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 14

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 14-1 CH₃ Cl Cl Cl Cl 14-2 CH₃ Cl —CH₂-iPr—CH₂-iPr —CH₂-iPr 14-3 CH₃ —CH₂-iPr Cl —CH₂-iPr —CH₂-iPr 14-4 CH₃—CH₂-iPr —CH₂-iPr Cl —CH₂-iPr 14-5 CH₃ —CH₂-iPr —CH₂-iPr —CH₂-iPr Cl14-6 CH₃ —CH₂-iPr Cl —CH₂-iPr Cl 14-7 CH₃ Cl —CH₂-iPr Cl —CH₂-iPr 14-8CH₃ —CH₂-iPr Cl Cl —CH₂-iPr 14-9 CH₃ Cl Cl —CH₂-iPr —CH₂-iPr 14-10 CH₃—CH₂-iPr —CH₂-iPr Cl Cl 14-11 CH₃ Cl —CH₂-iPr —CH₂-iPr Cl 14-12 CH₃—CH₂-iPr Cl Cl Cl 14-13 CH₃ Cl —CH₂-iPr Cl Cl 14-14 CH₃ Cl Cl —CH₂-iPrCl 14-15 CH₃ Cl Cl Cl —CH₂-iPr 14-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 14-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 14-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 14-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 14-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl14-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 14-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 14-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 14-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 14-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl14-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 14-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 14-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 14-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 14-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 14-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 14-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 14-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 14-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 14-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 14-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 14-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 14-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂14-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 14-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 14-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 14-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 14-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 14-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 14-45CH₃ n-Propyl Cl n-Propyl n-Propyl 14-46 CH₃ n-Propyl n-Propyl Cln-Propyl 14-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 14-48 CH₃ n-Propyl Cln-Propyl Cl 14-49 CH₃ Cl n-Propyl Cl n-Propyl 14-50 CH₃ n-Propyl Cl Cln-Propyl 14-51 CH₃ Cl Cl n-Propyl n-Propyl 14-52 CH₃ n-Propyl n-PropylCl Cl 14-53 CH₃ Cl n-Propyl n-Propyl Cl 14-54 CH₃ n-Propyl Cl Cl Cl14-55 CH₃ Cl n-Propyl Cl Cl 14-56 CH₃ Cl Cl n-Propyl Cl 14-57 CH₃ Cl ClCl n-Propyl 14-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 14-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 14-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂14-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 14-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 14-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 14-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 14-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃14-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 14-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 14-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 14-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 15

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 15-1 CH₃ Cl Cl Cl Cl 15-2 CH₃ Cl —CH₂-iPr—CH₂-iPr —CH₂-iPr 15-3 CH₃ —CH₂-iPr Cl —CH₂-iPr —CH₂-iPr 15-4 CH₃—CH₂-iPr —CH₂-iPr Cl —CH₂-iPr 15-5 CH₃ —CH₂-iPr —CH₂-iPr —CH₂-iPr Cl15-6 CH₃ —CH₂-iPr Cl —CH₂-iPr Cl 15-7 CH₃ Cl —CH₂-iPr Cl —CH₂-iPr 15-8CH₃ —CH₂-iPr Cl Cl —CH₂-iPr 15-9 CH₃ Cl Cl —CH₂-iPr —CH₂-iPr 15-10 CH₃—CH₂-iPr —CH₂-iPr Cl Cl 15-11 CH₃ Cl —CH₂-iPr —CH₂-iPr Cl 15-12 CH₃—CH₂-iPr Cl Cl Cl 15-13 CH₃ Cl —CH₂-iPr Cl Cl 15-14 CH₃ Cl Cl —CH₂-iPrCl 15-15 CH₃ Cl Cl Cl —CH₂-iPr 15-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 15-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 15-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 15-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 15-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl15-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 15-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 15-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 15-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 15-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl15-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 15-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 15-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 15-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 15-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 15-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 15-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 15-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 15-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 15-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 15-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 15-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 15-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂15-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 15-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 15-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 15-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 15-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 15-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 15-45CH₃ n-Propyl Cl n-Propyl n-Propyl 15-46 CH₃ n-Propyl n-Propyl Cln-Propyl 15-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 15-48 CH₃ n-Propyl Cln-Propyl Cl 15-49 CH₃ Cl n-Propyl Cl n-Propyl 15-50 CH₃ n-Propyl Cl Cln-Propyl 15-51 CH₃ Cl Cl n-Propyl n-Propyl 15-52 CH₃ n-Propyl n-PropylCl Cl 15-53 CH₃ Cl n-Propyl n-Propyl Cl 15-54 CH₃ n-Propyl Cl Cl Cl15-55 CH₃ Cl n-Propyl Cl Cl 15-56 CH₃ Cl Cl n-Propyl Cl 15-57 CH₃ Cl ClCl n-Propyl 15-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 15-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 15-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂15-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 15-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 15-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 15-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 15-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃15-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 15-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 15-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 15-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 16

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 16-1 CH₃ Cl Cl Cl Cl 16-2 CH₃ Cl —CH₂-iPr—CH₂-iPr —CH₂-iPr 16-3 CH₃ —CH₂-iPr Cl —CH₂-iPr —CH₂-iPr 16-4 CH₃—CH₂-iPr —CH₂-iPr Cl —CH₂-iPr 16-5 CH₃ —CH₂-iPr —CH₂-iPr —CH₂-iPr Cl16-6 CH₃ —CH₂-iPr Cl —CH₂-iPr Cl 16-7 CH₃ Cl —CH₂-iPr Cl —CH₂-iPr 16-8CH₃ —CH₂-iPr Cl Cl —CH₂-iPr 16-9 CH₃ Cl Cl —CH₂-iPr —CH₂-iPr 16-10 CH₃—CH₂-iPr —CH₂-iPr Cl Cl 16-11 CH₃ Cl —CH₂-iPr —CH₂-iPr Cl 16-12 CH₃—CH₂-iPr Cl Cl Cl 16-13 CH₃ Cl —CH₂-iPr Cl Cl 16-14 CH₃ Cl Cl —CH₂-iPrCl 16-15 CH₃ Cl Cl Cl —CH₂-iPr 16-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 16-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 16-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 16-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 16-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl16-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 16-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 16-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 16-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 16-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl16-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 16-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 16-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 16-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 16-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 16-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 16-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 16-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 16-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 16-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 16-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 16-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 16-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂16-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 16-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 16-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 16-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 16-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 16-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 16-45CH₃ n-Propyl Cl n-Propyl n-Propyl 16-46 CH₃ n-Propyl n-Propyl Cln-Propyl 16-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 16-48 CH₃ n-Propyl Cln-Propyl Cl 16-49 CH₃ Cl n-Propyl Cl n-Propyl 16-50 CH₃ n-Propyl Cl Cln-Propyl 16-51 CH₃ Cl Cl n-Propyl n-Propyl 16-52 CH₃ n-Propyl n-PropylCl Cl 16-53 CH₃ Cl n-Propyl n-Propyl Cl 16-54 CH₃ n-Propyl Cl Cl Cl16-55 CH₃ Cl n-Propyl Cl Cl 16-56 CH₃ Cl Cl n-Propyl Cl 16-57 CH₃ Cl ClCl n-Propyl 16-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 16-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 16-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂16-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 16-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 16-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 16-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 16-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃16-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 16-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 16-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 16-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 17

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 17-1 CH₃ Cl Cl Cl Cl 17-2 CH₃ Cl —CH₂-iPr—CH₂-iPr —CH₂-iPr 17-3 CH₃ —CH₂-iPr Cl —CH₂-iPr —CH₂-iPr 174 CH₃—CH₂-iPr —CH₂-iPr Cl —CH₂-iPr 17-5 CH₃ —CH₂-iPr —CH₂-iPr —CH₂-iPr Cl17-6 CH₃ —CH₂-iPr Cl —CH₂-iPr Cl 17-7 CH₃ Cl —CH₂-iPr Cl —CH₂-iPr 17-8CH₃ —CH₂-iPr Cl Cl —CH₂-iPr 17-9 CH₃ Cl Cl —CH₂-iPr —CH₂-iPr 17-10 CH₃—CH₂-iPr —CH₂-iPr Cl Cl 17-11 CH₃ Cl —CH₂-iPr —CH₂-iPr Cl 17-12 CH₃—CH₂-iPr Cl Cl Cl 17-13 CH₃ Cl —CH₂-iPr Cl Cl 17-14 CH₃ Cl Cl —CH₂-iPrCl 17-15 CH₃ Cl Cl Cl —CH₂-iPr 17-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 17-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 17-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 17-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 17-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl17-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 17-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 17-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 17-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 17-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl17-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 17-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 17-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 17-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 17-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 17-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 17-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 17-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 17-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 17-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 17-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 17-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 17-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂17-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 17-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 17-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 17-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 17-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 17-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 17-45CH₃ n-Propyl Cl n-Propyl n-Propyl 17-46 CH₃ n-Propyl n-Propyl Cln-Propyl 17-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 17-48 CH₃ n-Propyl Cln-Propyl Cl 17-49 CH₃ Cl n-Propyl Cl n-Propyl 17-50 CH₃ n-Propyl Cl Cln-Propyl 17-51 CH₃ Cl Cl n-Propyl n-Propyl 17-52 CH₃ n-Propyl n-PropylCl Cl 17-53 CH₃ Cl n-Propyl n-Propyl Cl 17-54 CH₃ n-Propyl Cl Cl Cl17-55 CH₃ Cl n-Propyl Cl Cl 17-56 CH₃ Cl Cl n-Propyl Cl 17-57 CH₃ Cl ClCl n-Propyl 17-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 17-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 17-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂17-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 17-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 17-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 17-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 17-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃17-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 17-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 17-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 17-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 18

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 18-1 CH₃ Cl Cl Cl Cl 18-2 CH₃ Cl —CH₂-iPr—CH₂-iPr —CH₂-iPr 18-3 CH₃ —CH₂-iPr Cl —CH₂-iPr —CH₂-iPr 18-4 CH₃—CH₂-iPr —CH₂-iPr Cl —CH₂-iPr 18-5 CH₃ —CH₂-iPr —CH₂-iPr —CH₂-iPr Cl18-6 CH₃ —CH₂-iPr Cl —CH₂-iPr Cl 18-7 CH₃ Cl —CH₂-iPr Cl —CH₂-iPr 18-8CH₃ —CH₂-iPr Cl Cl —CH₂-iPr 18-9 CH₃ Cl Cl —CH₂-iPr —CH₂-iPr 18-10 CH₃—CH₂-iPr —CH₂-iPr Cl Cl 18-11 CH₃ Cl —CH₂-iPr —CH₂-iPr Cl 18-12 CH₃—CH₂-iPr Cl Cl Cl 18-13 CH₃ Cl —CH₂-iPr Cl Cl 18-14 CH₃ Cl Cl —CH₂-iPrCl 18-15 CH₃ Cl Cl Cl —CH₂-iPr 18-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 18-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 18-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 18-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 18-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl18-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 18-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 18-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 18-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 18-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl18-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 18-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 18-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 18-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 18-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 18-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 18-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 18-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 18-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 18-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 18-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 18-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 18-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂18-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 18-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 18-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 18-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 18-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 18-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 18-45CH₃ n-Propyl Cl n-Propyl n-Propyl 18-46 CH₃ n-Propyl n-Propyl Cln-Propyl 18-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 18-48 CH₃ n-Propyl Cln-Propyl Cl 18-49 CH₃ Cl n-Propyl Cl n-Propyl 18-50 CH₃ n-Propyl Cl Cln-Propyl 18-51 CH₃ Cl Cl n-Propyl n-Propyl 18-52 CH₃ n-Propyl n-PropylCl Cl 18-53 CH₃ Cl n-Propyl n-Propyl Cl 18-54 CH₃ n-Propyl Cl Cl Cl18-55 CH₃ Cl n-Propyl Cl Cl 18-56 CH₃ Cl Cl n-Propyl Cl 18-57 CH₃ Cl ClCl n-Propyl 18-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 18-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 18-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂18-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 18-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 18-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 18-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 18-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃18-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 18-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 18-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 18-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 19

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 19-1 CH₃ Cl Cl Cl Cl 19-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 19-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 19-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 19-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl19-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 19-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 19-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 19-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 19-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 19-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 19-12 CH₃—CH₂—iPr Cl Cl Cl 19-13 CH₃ Cl —CH₂—iPr Cl Cl 19-14 CH₃ Cl Cl —CH₂—iPrCl 19-15 CH₃ Cl Cl Cl —CH₂—iPr 19-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 19-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 19-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 19-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 19-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl19-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 19-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 19-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 19-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 19-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl19-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 19-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 19-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 19-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 19-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 19-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 19-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 19-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 19-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 19-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 19-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 19-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 19-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂19-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 19-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 19-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 19-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 19-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 19-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 19-45CH₃ n-Propyl Cl n-Propyl n-Propyl 19-46 CH₃ n-Propyl n-Propyl Cln-Propyl 19-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 19-48 CH₃ n-Propyl Cln-Propyl Cl 19-49 CH₃ Cl n-Propyl Cl n-Propyl 19-50 CH₃ n-Propyl Cl Cln-Propyl 19-51 CH₃ Cl Cl n-Propyl n-Propyl 19-52 CH₃ n-Propyl n-PropylCl Cl 19-53 CH₃ Cl n-Propyl n-Propyl Cl 19-54 CH₃ n-Propyl Cl Cl Cl19-55 CH₃ Cl n-Propyl Cl Cl 19-56 CH₃ Cl Cl n-Propyl Cl 19-57 CH₃ Cl ClCl n-Propyl 19-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 19-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 19-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂19-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 19-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 19-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 19-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 19-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃19-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 19-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 19-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 19-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 20 Compounds of formula (I), wherein Cy¹ and Cy² are3,4,5-trifluorophenyl; R′, R″, R′″ and R″″ are each independentlyhydrogen or methyl; and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd #R^(a)/R^(b) R¹ R² R³ R⁴ 20-1 CH₃ Cl Cl Cl Cl 20-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 20-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 20-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 20-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl20-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 20-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 20-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 20-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 20-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 20-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 20-12 CH₃—CH₂—iPr Cl Cl Cl 20-13 CH₃ Cl —CH₂—iPr Cl Cl 20-14 CH₃ Cl Cl —CH₂—iPrCl 20-15 CH₃ Cl Cl Cl —CH₂—iPr 20-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 20-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 20-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 20-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 20-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl20-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 20-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 20-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 20-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 20-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl20-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 20-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 20-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 20-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 20-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 20-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 20-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 20-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 20-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 20-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 20-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 20-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 20-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂20-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 20-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 20-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 20-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 20-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 20-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 20-45CH₃ n-Propyl Cl n-Propyl n-Propyl 20-46 CH₃ n-Propyl n-Propyl Cln-Propyl 20-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 20-48 CH₃ n-Propyl Cln-Propyl Cl 20-49 CH₃ Cl n-Propyl Cl n-Propyl 20-50 CH₃ n-Propyl Cl Cln-Propyl 20-51 CH₃ Cl Cl n-Propyl n-Propyl 20-52 CH₃ n-Propyl n-PropylCl Cl 20-53 CH₃ Cl n-Propyl n-Propyl Cl 20-54 CH₃ n-Propyl Cl Cl Cl20-55 CH₃ Cl n-Propyl Cl Cl 20-56 CH₃ Cl Cl n-Propyl Cl 20-57 CH₃ Cl ClCl n-Propyl 20-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 20-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 20-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂20-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 20-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 20-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 20-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 20-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃20-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 20-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 20-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 20-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 21 Compounds of formula (I), wherein Cy¹ and Cy² arep-aminophenyl; R′, R″, R′″ and R″″ are each independently hydrogen ormethyl; and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd # R^(a)/R^(b)R¹ R² R³ R⁴ 21-1 CH₃ Cl Cl Cl Cl 21-2 CH₃ Cl —CH₂—iPr —CH₂—iPr —CH₂—iPr21-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 21-4 CH₃ —CH₂—iPr —CH₂—iPr Cl—CH₂—iPr 21-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 21-6 CH₃ —CH₂—iPr Cl—CH₂—iPr Cl 21-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 21-8 CH₃ —CH₂—iPr Cl Cl—CH₂—iPr 21-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 21-10 CH₃ —CH₂—iPr —CH₂—iPr ClCl 21-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 21-12 CH₃ —CH₂—iPr Cl Cl Cl 21-13CH₃ Cl —CH₂—iPr Cl Cl 21-14 CH₃ Cl Cl —CH₂—iPr Cl 21-15 CH₃ Cl Cl Cl—CH₂—iPr 21-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 21-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 21-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 21-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 21-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 21-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 21-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃21-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 21-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 21-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 21-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 21-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 21-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 21-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 21-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 21-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 21-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 21-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 21-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 21-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 21-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 21-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 21-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂21-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 21-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 21-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 21-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 21-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 21-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 21-45CH₃ n-Propyl Cl n-Propyl n-Propyl 21-46 CH₃ n-Propyl n-Propyl Cln-Propyl 21-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 21-48 CH₃ n-Propyl Cln-Propyl Cl 21-49 CH₃ Cl n-Propyl Cl n-Propyl 21-50 CH₃ n-Propyl Cl Cln-Propyl 21-51 CH₃ Cl Cl n-Propyl n-Propyl 21-52 CH₃ n-Propyl n-PropylCl Cl 21-53 CH₃ Cl n-Propyl n-Propyl Cl 21-54 CH₃ n-Propyl Cl Cl Cl21-55 CH₃ Cl n-Propyl Cl Cl 21-56 CH₃ Cl Cl n-Propyl Cl 21-57 CH₃ Cl ClCl n-Propyl 21-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 21-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 21-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂21-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 21-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 21-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 21-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 21-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃21-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 21-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 21-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 21-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 22 Compounds of formula (I), wherein Cy¹ and Cy² are p-iodophenyl;R′, R″, R′″ and R″″ are each independently hydrogen or methyl; andR^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴22-1 CH₃ Cl Cl Cl Cl 22-2 CH₃ Cl —CH₂—iPr —CH₂—iPr —CH₂—iPr 22-3 CH₃—CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 22-4 CH₃ —CH₂—iPr —CH₂—iPr Cl —CH₂—iPr22-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 22-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl22-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 22-8 CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 22-9CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 22-10 CH₃ —CH₂—iPr —CH₂—iPr Cl Cl 22-11 CH₃Cl —CH₂—iPr —CH₂—iPr Cl 22-12 CH₃ —CH₂—iPr Cl Cl Cl 22-13 CH₃ Cl—CH₂—iPr Cl Cl 22-14 CH₃ Cl Cl —CH₂—iPr Cl 22-15 CH₃ Cl Cl Cl —CH₂—iPr22-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 22-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 22-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 22-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 22-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 22-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 22-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃22-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 22-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 22-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 22-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 22-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 22-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 22-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 22-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 22-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 22-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 22-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 22-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 22-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 22-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 22-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 22-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂22-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 22-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 22-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 22-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 22-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 22-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 22-45CH₃ n-Propyl Cl n-Propyl n-Propyl 22-46 CH₃ n-Propyl n-Propyl Cln-Propyl 22-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 22-48 CH₃ n-Propyl Cln-Propyl Cl 22-49 CH₃ Cl n-Propyl Cl n-Propyl 22-50 CH₃ n-Propyl Cl Cln-Propyl 22-51 CH₃ Cl Cl n-Propyl n-Propyl 22-52 CH₃ n-Propyl n-PropylCl Cl 22-53 CH₃ Cl n-Propyl n-Propyl Cl 22-54 CH₃ n-Propyl Cl Cl Cl22-55 CH₃ Cl n-Propyl Cl Cl 22-56 CH₃ Cl Cl n-Propyl Cl 22-57 CH₃ Cl ClCl n-Propyl 22-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 22-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 22-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂22-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 22-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 22-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 22-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 22-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃22-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 22-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 22-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 22-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 23 Compounds of formula (I), wherein Cy¹ and Cy² arep-bromophenyl; R′, R″, R′″ and R″″ are each independently hydrogen ormethyl; and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd # R^(a)/R^(b)R¹ R² R³ R⁴ 23-1 CH₃ Cl Cl Cl Cl 23-2 CH₃ Cl —CH₂—iPr —CH₂—iPr —CH₂—iPr23-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 23-4 CH₃ —CH₂—iPr —CH₂—iPr Cl—CH₂—iPr 23-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 23-6 CH₃ —CH₂—iPr Cl—CH₂—iPr Cl 23-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 23-8 CH₃ —CH₂—iPr Cl Cl—CH₂—iPr 23-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 23-10 CH₃ —CH₂—iPr —CH₂—iPr ClCl 23-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 23-12 CH₃ —CH₂—iPr Cl Cl Cl 23-13CH₃ Cl —CH₂—iPr Cl Cl 23-14 CH₃ Cl Cl —CH₂—iPr Cl 23-15 CH₃ Cl Cl Cl—CH₂—iPr 23-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 23-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 23-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 23-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 23-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 23-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 23-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃23-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 23-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 23-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 23-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 23-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 23-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 23-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 23-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 23-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 23-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 23-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 23-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 23-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 23-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 23-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 23-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂23-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 23-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 23-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 23-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 23-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 23-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 23-45CH₃ n-Propyl Cl n-Propyl n-Propyl 23-46 CH₃ n-Propyl n-Propyl Cln-Propyl 23-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 23-48 CH₃ n-Propyl Cln-Propyl Cl 23-49 CH₃ Cl n-Propyl Cl n-Propyl 23-50 CH₃ n-Propyl Cl Cln-Propyl 23-51 CH₃ Cl Cl n-Propyl n-Propyl 23-52 CH₃ n-Propyl n-PropylCl Cl 23-53 CH₃ Cl n-Propyl n-Propyl Cl 23-54 CH₃ n-Propyl Cl Cl Cl23-55 CH₃ Cl n-Propyl Cl Cl 23-56 CH₃ Cl Cl n-Propyl Cl 23-57 CH₃ Cl ClCl n-Propyl 23-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 23-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 23-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂23-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 23-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 23-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 23-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 23-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃23-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 23-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 23-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 23-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 24 Compounds of formula (I), wherein Cy¹ and Cy² arep-cyanophenyl; R′, R″, R′″ and R″″ are each independently hydrogen ormethyl; and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd # R^(a)/R^(b)R¹ R² R³ R⁴ 24-1 CH₃ Cl Cl Cl Cl 24-2 CH₃ Cl —CH₂—iPr —CH₂—iPr —CH₂—iPr24-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 24-4 CH₃ —CH₂—iPr —CH₂—iPr Cl—CH₂—iPr 24-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 24-6 CH₃ —CH₂—iPr Cl—CH₂—iPr Cl 24-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 24-8 CH₃ —CH₂—iPr Cl Cl—CH₂—iPr 24-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 24-10 CH₃ —CH₂—iPr —CH₂—iPr ClCl 24-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 24-12 CH₃ —CH₂—iPr Cl Cl Cl 24-13CH₃ Cl —CH₂—iPr Cl Cl 24-14 CH₃ Cl Cl —CH₂—iPr Cl 24-15 CH₃ Cl Cl Cl—CH₂—iPr 24-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 24-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 24-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 24-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 24-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 24-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 24-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃24-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 24-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 24-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 24-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 24-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 24-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 24-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 24-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 24-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 24-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 24-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 24-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 24-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 24-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 24-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 24-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂24-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 24-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 24-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 24-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 24-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 24-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 24-45CH₃ n-Propyl Cl n-Propyl n-Propyl 24-46 CH₃ n-Propyl n-Propyl Cln-Propyl 24-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 24-48 CH₃ n-Propyl Cln-Propyl Cl 24-49 CH₃ Cl n-Propyl Cl n-Propyl 24-50 CH₃ n-Propyl Cl Cln-Propyl 24-51 CH₃ Cl Cl n-Propyl n-Propyl 24-52 CH₃ n-Propyl n-PropylCl Cl 24-53 CH₃ Cl n-Propyl n-Propyl Cl 24-54 CH₃ n-Propyl Cl Cl Cl24-55 CH₃ Cl n-Propyl Cl Cl 24-56 CH₃ Cl Cl n-Propyl Cl 24-57 CH₃ Cl ClCl n-Propyl 24-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 24-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 24-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂24-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 24-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 24-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 24-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 24-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃24-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 24-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 24-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 24-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 25

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 25-1 CH₃ Cl Cl Cl Cl 25-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 25-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 25-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 25-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl25-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 25-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 25-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 25-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 25-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 25-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 25-12 CH₃—CH₂—iPr Cl Cl Cl 25-13 CH₃ Cl —CH₂—iPr Cl Cl 25-14 CH₃ Cl Cl —CH₂—iPrCl 25-15 CH₃ Cl Cl Cl —CH₂—iPr 25-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 25-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 25-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 25-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 25-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl25-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 25-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 25-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 25-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 25-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl25-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 25-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 25-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 25-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 25-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 25-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 25-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 25-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 25-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 25-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 25-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 25-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 25-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂25-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 25-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 25-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 25-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 25-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 25-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 25-45CH₃ n-Propyl Cl n-Propyl n-Propyl 25-46 CH₃ n-Propyl n-Propyl Cln-Propyl 25-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 25-48 CH₃ n-Propyl Cln-Propyl Cl 25-49 CH₃ Cl n-Propyl Cl n-Propyl 25-50 CH₃ n-Propyl Cl Cln-Propyl 25-51 CH₃ Cl Cl n-Propyl n-Propyl 25-52 CH₃ n-Propyl n-PropylCl Cl 25-53 CH₃ Cl n-Propyl n-Propyl Cl 25-54 CH₃ n-Propyl Cl Cl Cl25-55 CH₃ Cl n-Propyl Cl Cl 25-56 CH₃ Cl Cl n-Propyl Cl 25-57 CH₃ Cl ClCl n-Propyl 25-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 25-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 25-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂25-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 25-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 25-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 25-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 25-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃25-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 25-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 25-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 25-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 26

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 26-1 CH₃ Cl Cl Cl Cl 26-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 26-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 26-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 26-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl26-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 26-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 26-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 26-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 26-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 26-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 26-12 CH₃—CH₂—iPr Cl Cl Cl 26-13 CH₃ Cl —CH₂—iPr Cl Cl 26-14 CH₃ Cl Cl —CH₂—iPrCl 26-15 CH₃ Cl Cl Cl —CH₂—iPr 26-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 26-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 26-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 26-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 26-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl26-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 26-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 26-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 26-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 26-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl26-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 26-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 26-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 26-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 26-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 26-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 26-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 26-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 26-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 26-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 26-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 26-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 26-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂26-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 26-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 26-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 26-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 26-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 26-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 26-45CH₃ n-Propyl Cl n-Propyl n-Propyl 26-46 CH₃ n-Propyl n-Propyl Cln-Propyl 26-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 26-48 CH₃ n-Propyl Cln-Propyl Cl 26-49 CH₃ Cl n-Propyl Cl n-Propyl 26-50 CH₃ n-Propyl Cl Cln-Propyl 26-51 CH₃ Cl Cl n-Propyl n-Propyl 26-52 CH₃ n-Propyl n-PropylCl Cl 26-53 CH₃ Cl n-Propyl n-Propyl Cl 26-54 CH₃ n-Propyl Cl Cl Cl26-55 CH₃ Cl n-Propyl Cl Cl 26-56 CH₃ Cl Cl n-Propyl Cl 26-57 CH₃ Cl ClCl n-Propyl 26-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 26-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 26-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂26-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 26-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 26-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 26-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 26-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃26-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 26-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 26-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 26-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 27

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 27-1 CH₃ Cl Cl Cl Cl 27-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 27-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 27-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 27-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl27-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 27-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 27-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 27-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 27-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 27-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 27-12 CH₃—CH₂—iPr Cl Cl Cl 27-13 CH₃ Cl —CH₂—iPr Cl Cl 27-14 CH₃ Cl Cl —CH₂—iPrCl 27-15 CH₃ Cl Cl Cl —CH₂—iPr 27-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 27-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 27-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 27-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 27-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl27-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 27-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 27-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 27-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 27-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl27-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 27-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 27-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 27-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 27-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 27-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 27-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 27-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 27-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 27-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 27-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 27-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 27-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂27-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 27-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 27-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 27-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 27-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 27-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 27-45CH₃ n-Propyl Cl n-Propyl n-Propyl 27-46 CH₃ n-Propyl n-Propyl Cln-Propyl 27-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 27-48 CH₃ n-Propyl Cln-Propyl Cl 27-49 CH₃ Cl n-Propyl Cl n-Propyl 27-50 CH₃ n-Propyl Cl Cln-Propyl 27-51 CH₃ Cl Cl n-Propyl n-Propyl 27-52 CH₃ n-Propyl n-PropylCl Cl 27-53 CH₃ Cl n-Propyl n-Propyl Cl 27-54 CH₃ n-Propyl Cl Cl Cl27-55 CH₃ Cl n-Propyl Cl Cl 27-56 CH₃ Cl Cl n-Propyl Cl 27-57 CH₃ Cl ClCl n-Propyl 27-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 27-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 27-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂27-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 27-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 27-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 27-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 27-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃27-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 27-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 27-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 27-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 28 Compounds of formula (I), wherein Cy¹ and Cy² arep-nitrophenyl; R′, R″, R′″ and R″″ are each independently hydrogen ormethyl; and R^(a), R^(b) and R¹ to R⁴ are as shown. Cmpd # R^(a)/R^(b)R¹ R² R³ R⁴ 28-1 CH₃ Cl Cl Cl Cl 28-2 CH₃ Cl —CH₂—iPr —CH₂—iPr —CH₂—iPr28-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 28-4 CH₃ —CH₂—iPr —CH₂—iPr Cl—CH₂—iPr 28-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl 28-6 CH₃ —CH₂—iPr Cl—CH₂—iPr Cl 28-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 28-8 CH₃ —CH₂—iPr Cl Cl—CH₂—iPr 28-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 28-10 CH₃ —CH₂—iPr —CH₂—iPr ClCl 28-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 28-12 CH₃ —CH₂—iPr Cl Cl Cl 28-13CH₃ Cl —CH₂—iPr Cl Cl 28-14 CH₃ Cl Cl —CH₂—iPr Cl 28-15 CH₃ Cl Cl Cl—CH₂—iPr 28-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 28-17 CH₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 28-18 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 28-19 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 28-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 28-21 CH₃ Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 28-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃28-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 28-24 CH₃ Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 28-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl 28-26 CH₃—CH₂—C(CH₃)₃ Cl Cl Cl 28-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 28-28 CH₃ Cl Cl—CH₂—C(CH₃)₃ Cl 28-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 28-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 28-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 28-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 28-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 28-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 28-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 28-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 28-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 28-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂28-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 28-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 28-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 28-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 28-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 28-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 28-45CH₃ n-Propyl Cl n-Propyl n-Propyl 28-46 CH₃ n-Propyl n-Propyl Cln-Propyl 28-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 28-48 CH₃ n-Propyl Cln-Propyl Cl 28-49 CH₃ Cl n-Propyl Cl n-Propyl 28-50 CH₃ n-Propyl Cl Cln-Propyl 28-51 CH₃ Cl Cl n-Propyl n-Propyl 28-52 CH₃ n-Propyl n-PropylCl Cl 28-53 CH₃ Cl n-Propyl n-Propyl Cl 28-54 CH₃ n-Propyl Cl Cl Cl28-55 CH₃ Cl n-Propyl Cl Cl 28-56 CH₃ Cl Cl n-Propyl Cl 28-57 CH₃ Cl ClCl n-Propyl 28-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 28-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 28-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂28-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 28-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 28-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 28-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 28-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃28-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 28-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 28-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 28-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 29

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 29-1 CH₃ Cl Cl Cl Cl 29-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 29-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 29-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 29-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl29-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 29-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 29-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 29-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 29-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 29-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 29-12 CH₃—CH₂—iPr Cl Cl Cl 29-13 CH₃ Cl —CH₂—iPr Cl Cl 29-14 CH₃ Cl Cl —CH₂—iPrCl 29-15 CH₃ Cl Cl Cl —CH₂—iPr 29-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 29-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 29-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 29-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 29-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl29-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 29-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 29-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 29-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 29-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl29-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 29-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 29-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 29-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 29-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 29-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 29-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 29-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 29-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 29-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 29-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 29-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 29-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂29-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 29-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 29-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 29-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 29-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 29-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 29-45CH₃ n-Propyl Cl n-Propyl n-Propyl 29-46 CH₃ n-Propyl n-Propyl Cln-Propyl 29-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 29-48 CH₃ n-Propyl Cln-Propyl Cl 29-49 CH₃ Cl n-Propyl Cl n-Propyl 29-50 CH₃ n-Propyl Cl Cln-Propyl 29-51 CH₃ Cl Cl n-Propyl n-Propyl 29-52 CH₃ n-Propyl n-PropylCl Cl 29-53 CH₃ Cl n-Propyl n-Propyl Cl 29-54 CH₃ n-Propyl Cl Cl Cl29-55 CH₃ Cl n-Propyl Cl Cl 29-56 CH₃ Cl Cl n-Propyl Cl 29-57 CH₃ Cl ClCl n-Propyl 29-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 29-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 29-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂29-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 29-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 29-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 29-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 29-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃29-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 29-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 29-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 29-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 30

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 30-1 CH₃ Cl Cl Cl Cl 30-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 30-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 30-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 30-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl30-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 30-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 30-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 30-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 30-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 30-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 30-12 CH₃—CH₂—iPr Cl Cl Cl 30-13 CH₃ Cl —CH₂—iPr Cl Cl 30-14 CH₃ Cl Cl —CH₂—iPrCl 30-15 CH₃ Cl Cl Cl —CH₂—iPr 30-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 30-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 30-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 30-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 30-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl30-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 30-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 30-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 30-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 30-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl30-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 30-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 30-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 30-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 30-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 30-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 30-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 30-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 30-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 30-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 30-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 30-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 30-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂30-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 30-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 30-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 30-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 30-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 30-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 30-45CH₃ n-Propyl Cl n-Propyl n-Propyl 30-46 CH₃ n-Propyl n-Propyl Cln-Propyl 30-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 30-48 CH₃ n-Propyl Cln-Propyl Cl 30-49 CH₃ Cl n-Propyl Cl n-Propyl 30-50 CH₃ n-Propyl Cl Cln-Propyl 30-51 CH₃ Cl Cl n-Propyl n-Propyl 30-52 CH₃ n-Propyl n-PropylCl Cl 30-53 CH₃ Cl n-Propyl n-Propyl Cl 30-54 CH₃ n-Propyl Cl Cl Cl30-55 CH₃ Cl n-Propyl Cl Cl 30-56 CH₃ Cl Cl n-Propyl Cl 30-57 CH₃ Cl ClCl n-Propyl 30-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 30-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 30-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂30-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 30-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 30-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 30-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 30-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃30-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 30-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 30-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 30-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 31

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 31-1 CH₃ Cl Cl Cl Cl 31-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 31-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 31-4 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 31-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl31-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 31-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 31-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 31-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 31-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 31-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 31-12 CH₃—CH₂—iPr Cl Cl Cl 31-13 CH₃ Cl —CH₂—iPr Cl Cl 31-14 CH₃ Cl Cl —CH₂—iPrCl 31-15 CH₃ Cl Cl Cl —CH₂—iPr 31-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 31-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 31-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 31-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 31-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl31-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 31-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 31-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 31-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 31-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl31-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 31-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 31-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 31-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 31-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 31-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 31-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 31-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 31-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 31-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 31-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 31-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 31-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂31-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 31-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 31-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 31-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 31-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 31-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 31-45CH₃ n-Propyl Cl n-Propyl n-Propyl 31-46 CH₃ n-Propyl n-Propyl Cln-Propyl 31-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 31-48 CH₃ n-Propyl Cln-Propyl Cl 31-49 CH₃ Cl n-Propyl Cl n-Propyl 31-50 CH₃ n-Propyl Cl Cln-Propyl 31-51 CH₃ Cl Cl n-Propyl n-Propyl 31-52 CH₃ n-Propyl n-PropylCl Cl 31-53 CH₃ Cl n-Propyl n-Propyl Cl 31-54 CH₃ n-Propyl Cl Cl Cl31-55 CH₃ Cl n-Propyl Cl Cl 31-56 CH₃ Cl Cl n-Propyl Cl 31-57 CH₃ Cl ClCl n-Propyl 31-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 31-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 31-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂31-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 31-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 31-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 31-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 31-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃31-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 31-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 31-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 31-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 32 Compounds of formula (I), wherein Cy¹ and Cy² are

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 32-1  CH₃ Cl Cl Cl Cl 32-2  CH₃ Cl—CH₂—iPr —CH₂—iPr —CH₂—iPr 32-3  CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 32-4 CH₃ —CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 32-5  CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPrCl 32-6  CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 32-7  CH₃ Cl —CH₂—iPr Cl —CH₂—iPr32-8  CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 32-9  CH₃ Cl Cl —CH₂—iPr —CH₂—iPr32-10 CH₃ —CH₂—iPr —CH₂—iPr Cl Cl 32-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl32-12 CH₃ —CH₂—iPr Cl Cl Cl 32-13 CH₃ Cl —CH₂—iPr Cl Cl 32-14 CH₃ Cl Cl—CH₂—iPr Cl 32-15 CH₃ Cl Cl Cl —CH₂—iPr 32-16 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 32-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 32-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 32-19CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 32-20 CH₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ Cl 32-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 32-22 CH₃—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 32-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl 32-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 32-25 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl Cl 32-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 32-27 CH₃ Cl—CH₂—C(CH₃)₃ Cl Cl 32-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 32-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 32-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 32-31CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 32-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 32-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 32-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 32-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 32-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂32-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 32-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 32-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 32-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 32-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 32-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 32-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 32-44 CH₃ Cl n-Propyln-Propyl n-Propyl 32-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 32-46 CH₃n-Propyl n-Propyl Cl n-Propyl 32-47 CH₃ n-Propyl n-Propyl n-Propyl Cl32-48 CH₃ n-Propyl Cl n-Propyl Cl 32-49 CH₃ Cl n-Propyl Cl n-Propyl32-50 CH₃ n-Propyl Cl Cl n-Propyl 32-51 CH₃ Cl Cl n-Propyl n-Propyl32-52 CH₃ n-Propyl n-Propyl Cl Cl 32-53 CH₃ Cl n-Propyl n-Propyl Cl32-54 CH₃ n-Propyl Cl Cl Cl 32-55 CH₃ Cl n-Propyl Cl Cl 32-56 CH₃ Cl Cln-Propyl Cl 32-57 CH₃ Cl Cl Cl n-Propyl 32-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 32-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 32-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 32-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl32-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 32-63 H —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 32-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 32-65 H Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 32-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃32-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 32-68 H Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 32-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 33 Compounds of formula (I), wherein Cy¹ and Cy² are

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 33-1  CH₃ Cl Cl Cl Cl 33-2  CH₃ Cl—CH₂—iPr —CH₂—iPr —CH₂—iPr 33-3  CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 33-4 CH₃ —CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 33-5  CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPrCl 33-6  CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 33-7  CH₃ Cl —CH₂—iPr Cl —CH₂—iPr33-8  CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 33-9  CH₃ Cl Cl —CH₂—iPr —CH₂—iPr33-10 CH₃ —CH₂—iPr —CH₂—iPr Cl Cl 33-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl33-12 CH₃ —CH₂—iPr Cl Cl Cl 33-13 CH₃ Cl —CH₂—iPr Cl Cl 33-14 CH₃ Cl Cl—CH₂—iPr Cl 33-15 CH₃ Cl Cl Cl —CH₂—iPr 33-16 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 33-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 33-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 33-19CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 33-20 CH₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ Cl 33-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 33-22 CH₃—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 33-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl 33-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 33-25 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl Cl 33-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 33-27 CH₃ Cl—CH₂—C(CH₃)₃ Cl Cl 33-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 33-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 33-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 33-31CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 33-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 33-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 33-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 33-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 33-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂33- 37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 33-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 33-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 33-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 33-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 33-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 33-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 33-44 CH₃ Cl n-Propyln-Propyl n-Propyl 33-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 33-46 CH₃n-Propyl n-Propyl Cl n-Propyl 33-47 CH₃ n-Propyl n-Propyl n-Propyl Cl33-48 CH₃ n-Propyl Cl n-Propyl Cl 33-49 CH₃ Cl n-Propyl Cl n-Propyl33-50 CH₃ n-Propyl Cl Cl n-Propyl 33-51 CH₃ Cl Cl n-Propyl n-Propyl33-52 CH₃ n-Propyl n-Propyl Cl Cl 33-53 CH₃ Cl n-Propyl n-Propyl Cl33-54 CH₃ n-Propyl Cl Cl Cl 33-55 CH₃ Cl n-Propyl Cl Cl 33-56 CH₃ Cl Cln-Propyl Cl 33-57 CH₃ Cl Cl Cl n-Propyl 33-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 33-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 33-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 33-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl33-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 33-63 H —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 33-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 33-65 H Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 33-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃33-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 33-68 H Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 33-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 34 Compounds of formula (I), wherein Cy¹ and Cy² are

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 34-1 CH₃ Cl Cl Cl Cl 34-2 CH₃ Cl —CH₂—iPr—CH₂—iPr —CH₂—iPr 34-3 CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 344 CH₃—CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 34-5 CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPr Cl34-6 CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 34-7 CH₃ Cl —CH₂—iPr Cl —CH₂—iPr 34-8CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 34-9 CH₃ Cl Cl —CH₂—iPr —CH₂—iPr 34-10 CH₃—CH₂—iPr —CH₂—iPr Cl Cl 34-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl 34-12 CH₃—CH₂—iPr Cl Cl Cl 34-13 CH₃ Cl —CH₂—iPr Cl Cl 34-14 CH₃ Cl Cl —CH₂—iPrCl 34-15 CH₃ Cl Cl Cl —CH₂—iPr 34-16 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 34-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 34-18CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 34-19 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 34-20 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl34-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 34-22 CH₃ —CH₂—C(CH₃)₃ Cl Cl—CH₂—C(CH₃)₃ 34-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 34-24 CH₃ Cl Cl—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 34-25 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl34-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 34-27 CH₃ Cl —CH₂—C(CH₃)₃ Cl Cl 34-28CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 34-29 CH₃ Cl Cl Cl —CH₂—C(CH₃)₃ 34-30 CH₃ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF (CH₃)₂ 34-31 CH₃ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 34-32 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 34-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 34-34CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 34-35 CH₃ Cl —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ 34-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 34-37 CH₃ Cl—CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 34-38 CH₃ Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂34-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 34-40 CH₃ —CH₂CF(CH₃)₂ Cl ClCl 34-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 34-42 CH₃ Cl Cl —CH₂CF(CH₃)₂ Cl 34-43CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 34-44 CH₃ Cl n-Propyl n-Propyl n-Propyl 34-45CH₃ n-Propyl Cl n-Propyl n-Propyl 34-46 CH₃ n-Propyl n-Propyl Cln-Propyl 34-47 CH₃ n-Propyl n-Propyl n-Propyl Cl 34-48 CH₃ n-Propyl Cln-Propyl Cl 34-49 CH₃ Cl n-Propyl Cl n-Propyl 34-50 CH₃ n-Propyl Cl Cln-Propyl 34-51 CH₃ Cl Cl n-Propyl n-Propyl 34-52 CH₃ n-Propyl n-PropylCl Cl 34-53 CH₃ Cl n-Propyl n-Propyl Cl 34-54 CH₃ n-Propyl Cl Cl Cl34-55 CH₃ Cl n-Propyl Cl Cl 34-56 CH₃ Cl Cl n-Propyl Cl 34-57 CH₃ Cl ClCl n-Propyl 34-58 H —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 34-59 H Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 34-60 H —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂34-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl 34-62 H Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 34-63 H —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 34-64 H—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 34-65 H Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃34-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 34-67 H Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl 34-68 H Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 34-69 H—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 35 Compounds of formula (I), wherein Cy¹ and Cy² are

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 35-1  CH₃ Cl Cl Cl Cl 35-2  CH₃ Cl—CH₂—iPr —CH₂—iPr —CH₂—iPr 35-3  CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 35-4 CH₃ —CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 35-5  CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPrCl 35-6  CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 35-7  CH₃ Cl —CH₂—iPr Cl —CH₂—iPr35-8  CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 35-9  CH₃ Cl Cl —CH₂—iPr —CH₂—iPr35-10 CH₃ —CH₂—iPr —CH₂—iPr Cl Cl 35-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl35-12 CH₃ —CH₂—iPr Cl Cl Cl 35-13 CH₃ Cl —CH₂—iPr Cl Cl 35-14 CH₃ Cl Cl—CH₂—iPr Cl 35-15 CH₃ Cl Cl Cl —CH₂—iPr 35-16 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 35-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 35-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 35-19CH —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 35-20 CH₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ Cl 35-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 35-22 CH₃—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 35-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl 35-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 35-25 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl Cl 35-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 35-27 CH₃ Cl—CH₂—C(CH₃)₃ Cl Cl 35-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 35-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 35-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 35-31CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 35-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 35-33 CH —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 35-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 35-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 35-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂35-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 35-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 35-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 35-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 35-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 35-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 35-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 35-44 CH₃ Cl n-Propyln-Propyl n-Propyl 35-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 35-46 CH₃n-Propyl n-Propyl Cl n-Propyl 35-47 CH₃ n-Propyl n-Propyl n-Propyl Cl35-48 CH₃ n-Propyl Cl n-Propyl Cl 35-49 CH₃ Cl n-Propyl Cl n-Propyl35-50 CH₃ n-Propyl Cl Cl n-Propyl 35-51 CH₃ Cl Cl n-Propyl n-Propyl35-52 CH₃ n-Propyl n-Propyl Cl Cl 35-53 CH₃ Cl n-Propyl n-Propyl Cl35-54 CH₃ n-Propyl Cl Cl Cl 35-55 CH₃ Cl n-Propyl Cl Cl 35-56 CH₃ Cl Cln-Propyl Cl 35-57 CH₃ Cl Cl Cl n-Propyl 35-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 35-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 35-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 35-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl35-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 35-63 H —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 35-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 35-65 H Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 35-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃35-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 35-68 H Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 35-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 36 Compounds of formula (I), wherein Cy¹ and Cy² are

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 36-1  CH₃ Cl Cl Cl Cl 36-2  CH₃ Cl—CH₂—iPr —CH₂—iPr —CH₂—iPr 36-3  CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 36-4 CH₃ —CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 36-5  CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPrCl 36-6  CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 36-7  CH₃ Cl —CH₂—iPr Cl —CH₂—iPr36-8  CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 36-9  CH₃ Cl Cl —CH₂—iPr —CH₂—iPr36-10 CH₃ —CH₂—iPr —CH₂—iPr Cl Cl 36-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl36-12 CH₃ —CH₂—iPr Cl Cl Cl 36-13 CH₃ Cl —CH₂—iPr Cl Cl 36-14 CH₃ Cl Cl—CH₂—iPr Cl 36-15 CH₃ Cl Cl Cl —CH₂—iPr 36-16 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 36-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 36-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 36-19CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 36-20 CH₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ Cl 36-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 36-22 CH₃—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 36-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl 36-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 36-25 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl Cl 36-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 36-27 CH₃ Cl—CH₂—C(CH₃)₃ Cl Cl 36-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 36-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 36-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 36-31CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 36-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 36-33 CH —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 36-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 36-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 36-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂36-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 36-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 36-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 36-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 36-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 36-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 36-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 36-44 CH₃ Cl n-Propyln-Propyl n-Propyl 36-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 36-46 CH₃n-Propyl n-Propyl Cl n-Propyl 36-47 CH₃ n-Propyl n-Propyl n-Propyl Cl36-48 CH₃ n-Propyl Cl n-Propyl Cl 36-49 CH₃ Cl n-Propyl Cl n-Propyl36-50 CH₃ n-Propyl Cl Cl n-Propyl 36-51 CH₃ Cl Cl n-Propyl n-Propyl36-52 CH₃ n-Propyl n-Propyl Cl Cl 36-53 CH₃ Cl n-Propyl n-Propyl Cl36-54 CH₃ n-Propyl Cl Cl Cl 36-55 CH₃ Cl n-Propyl Cl Cl 36-56 CH₃ Cl Cln-Propyl Cl 36-57 CH₃ Cl Cl Cl n-Propyl 36-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 36-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 36-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 36-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl36-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 36-63 H —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 36-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 36-65 H Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 36-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃36-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 36-68 H Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 36-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 37 Compounds of formula (I), wherein Cy¹ and Cy² are

Cmpd # R^(a)/R^(b) R⁴ R² R³ R⁴ 37-1  CH₃ Cl Cl Cl Cl 37-2  CH₃ Cl—CH₂—iPr —CH₂—iPr —CH₂—iPr 37-3  CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 37-4 CH₃ —CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 37-5  CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPrCl 37-6  CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 37-7  CH₃ Cl —CH₂—iPr Cl —CH₂—iPr37-8  CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 37-9  CH₃ Cl Cl —CH₂—iPr —CH₂—iPr37-10 CH₃ —CH₂—iPr —CH₂—iPr Cl Cl 37-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl37-12 CH₃ —CH₂—iPr Cl Cl Cl 37-13 CH₃ Cl —CH₂—iPr Cl Cl 37-14 CH₃ Cl Cl—CH₂—iPr Cl 37-15 CH₃ Cl Cl Cl —CH₂—iPr 37-16 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 37-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 37-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 37-19CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 37-20 CH₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ Cl 37-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 37-22 CH₃—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 37-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl 37-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 37-25 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl Cl 37-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 37-27 CH₃ Cl—CH₂—C(CH₃)₃ Cl Cl 37-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 37-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 37-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 37-31CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 37-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 37-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 37-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 37-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 37-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂37-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 37-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 37-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 37-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 37-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 37-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 37-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 37-44 CH₃ Cl n-Propyln-Propyl n-Propyl 37-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 37-46 CH₃n-Propyl n-Propyl Cl n-Propyl 37-47 CH₃ n-Propyl n-Propyl n-Propyl Cl37-48 CH₃ n-Propyl Cl n-Propyl Cl 37-49 CH₃ Cl n-Propyl Cl n-Propyl37-50 CH₃ n-Propyl Cl Cl n-Propyl 37-51 CH₃ Cl Cl n-Propyl n-Propyl37-52 CH₃ n-Propyl n-Propyl Cl Cl 37-53 CH₃ Cl n-Propyl n-Propyl Cl37-54 CH₃ n-Propyl Cl Cl Cl 37-55 CH₃ Cl n-Propyl Cl Cl 37-56 CH₃ Cl Cln-Propyl Cl 37-57 CH₃ Cl Cl Cl n-Propyl 37-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 37-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 37-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 37-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl37-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 37-63 H —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 37-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 37-65 H Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 37-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃37-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 37-68 H Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 37-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

TABLE 38 Compounds of formula (I), wherein Cy¹ and Cy² are

Cmpd # R^(a)/R^(b) R¹ R² R³ R⁴ 38-1  CH₃ Cl Cl Cl Cl 38-2  CH₃ Cl—CH₂—iPr —CH₂—iPr —CH₂—iPr 38-3  CH₃ —CH₂—iPr Cl —CH₂—iPr —CH₂—iPr 38-4 CH₃ —CH₂—iPr —CH₂—iPr Cl —CH₂—iPr 38-5  CH₃ —CH₂—iPr —CH₂—iPr —CH₂—iPrCl 38-6  CH₃ —CH₂—iPr Cl —CH₂—iPr Cl 38-7  CH₃ Cl —CH₂—iPr Cl —CH₂—iPr38-8  CH₃ —CH₂—iPr Cl Cl —CH₂—iPr 38-9  CH₃ Cl Cl —CH₂—iPr —CH₂—iPr38-10 CH₃ —CH₂—iPr —CH₂—iPr Cl Cl 38-11 CH₃ Cl —CH₂—iPr —CH₂—iPr Cl38-12 CH₃ —CH₂—iPr Cl Cl Cl 38-13 CH₃ Cl —CH₂—iPr Cl Cl 38-14 CH₃ Cl Cl—CH₂—iPr Cl 38-15 CH₃ Cl Cl Cl —CH₂—iPr 38-16 CH₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 38-17 CH₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 38-18 CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 38-19CH₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 38-20 CH₃ —CH₂—C(CH₃)₃ Cl—CH₂—C(CH₃)₃ Cl 38-21 CH₃ Cl —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 38-22 CH₃—CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃ 38-23 CH₃ Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃Cl 38-24 CH₃ Cl Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ 38-25 CH₃ —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ Cl Cl 38-26 CH₃ —CH₂—C(CH₃)₃ Cl Cl Cl 38-27 CH₃ Cl—CH₂—C(CH₃)₃ Cl Cl 38-28 CH₃ Cl Cl —CH₂—C(CH₃)₃ Cl 38-29 CH₃ Cl Cl Cl—CH₂—C(CH₃)₃ 38-30 CH₃ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ —CHCF(CH₃)₂ 38-31CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 38-32 CH₃ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 38-33 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl 38-34 CH₃ —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ Cl 38-35 CH₃ Cl—CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 38-36 CH₃ —CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂38-37 CH₃ Cl —CH₂CF(CH₃)₂ CH₂CF(CH₃)₂ Cl 38-38 CH₃ Cl Cl —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ 38-39 CH₃ —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl Cl 38-40 CH₃—CH₂CF(CH₃)₂ Cl Cl Cl 38-41 CH₃ Cl —CH₂CF(CH₃)₂ Cl Cl 38-42 CH₃ Cl Cl—CH₂CF(CH₃)₂ Cl 38-43 CH₃ Cl Cl Cl —CH₂CF(CH₃)₂ 38-44 CH₃ Cl n-Propyln-Propyl n-Propyl 38-45 CH₃ n-Propyl Cl n-Propyl n-Propyl 38-46 CH₃n-Propyl n-Propyl Cl n-Propyl 38-47 CH₃ n-Propyl n-Propyl n-Propyl Cl38-48 CH₃ n-Propyl Cl n-Propyl Cl 38-49 CH₃ Cl n-Propyl Cl n-Propyl38-50 CH₃ n-Propyl Cl Cl n-Propyl 38-51 CH₃ Cl Cl n-Propyl n-Propyl38-52 CH₃ n-Propyl n-Propyl Cl Cl 38-53 CH₃ Cl n-Propyl n-Propyl Cl38-54 CH₃ n-Propyl Cl Cl Cl 38-55 CH₃ Cl n-Propyl Cl Cl 38-56 CH₃ Cl Cln-Propyl Cl 38-57 CH₃ Cl Cl Cl n-Propyl 38-58 H —CH₂CF(CH₃)₂ Cl—CH₂CF(CH₃)₂ Cl 38-59 H Cl —CH₂CF(CH₃)₂ Cl —CH₂CF(CH₃)₂ 38-60 H—CH₂CF(CH₃)₂ Cl Cl —CH₂CF(CH₃)₂ 38-61 H Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ Cl38-62 H Cl Cl —CH₂CF(CH₃)₂ —CH₂CF(CH₃)₂ 38-63 H —CH₂CF(CH₃)₂—CH₂CF(CH₃)₂ Cl Cl 38-64 H —CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ Cl 38-65 H Cl—CH₂—C(CH₃)₃ Cl —CH₂—C(CH₃)₃ 38-66 H —CH₂—C(CH₃)₃ Cl Cl —CH₂—C(CH₃)₃38-67 H Cl —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl 38-68 H Cl Cl —CH₂—C(CH₃)₃—CH₂—C(CH₃)₃ 38-69 H —CH₂—C(CH₃)₃ —CH₂—C(CH₃)₃ Cl Cl

Particular embodiments of the compounds of the invention are furtherdescribed in Tables 39-1037 wherein the meaning of the variables Cy¹,Cy², R^(a), R^(b) and R¹ to R⁴ are as described in Tables 2-38, with theexception that group C1 in Tables 2-38 is replaced with the groups C2 toC28.

Table 39: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 2, with the exception that C1 is replaced by C2.

Table 40: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 3, with the exception that C1 is replaced by C2.

Table 41: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 4, with the exception that C1 is replaced by C2.

Table 42: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 5, with the exception that C1 is replaced by C2.

Table 43: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 6, with the exception that C1 is replaced by C2.

Table 44: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 7, with the exception that C1 is replaced by C2.

Table 45: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 8, with the exception that C1 is replaced by C2.

Table 46: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 9, with the exception that C1 is replaced by C2.

Table 47: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 10, with the exception that C1 is replaced by C2.

Table 48: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 11, with the exception that C1 is replaced by C2.

Table 49: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 12, with the exception that C1 is replaced by C2.

Table 50: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 13, with the exception that C1 is replaced by C2.

Table 51: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 14, with the exception that C1 is replaced by C2.

Table 52: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 15, with the exception that C1 is replaced by C2.

Table 53: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 16, with the exception that C1 is replaced by C2.

Table 54: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 17, with the exception that C1 is replaced by C2.

Table 55: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 18, with the exception that C1 is replaced by C2.

Table 56: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 19, with the exception that C1 is replaced by C2.

Table 57: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 20, with the exception that C1 is replaced by C2.

Table 58: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 21, with the exception that C1 is replaced by C2.

Table 59: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 22, with the exception that C1 is replaced by C2.

Table 60: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 23, with the exception that C1 is replaced by C2.

Table 61: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 24, with the exception that C1 is replaced by C2.

Table 62: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 25, with the exception that C1 is replaced by C2.

Table 63: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 26, with the exception that C1 is replaced by C2.

Table 64: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 27, with the exception that C1 is replaced by C2.

Table 65: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 28, with the exception that C1 is replaced by C2.

Table 66: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 29, with the exception that C1 is replaced by C2.

Table 67: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 30, with the exception that C1 is replaced by C2.

Table 68: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 31, with the exception that C1 is replaced by C2.

Table 69: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 32, with the exception that C1 is replaced by C2.

Table 70: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 33, with the exception that C1 is replaced by C2.

Table 71: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 34, with the exception that C1 is replaced by C2.

Table 72: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 35, with the exception that C1 is replaced by C2.

Table 73: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 36, with the exception that C1 is replaced by C2.

Table 74: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 37, with the exception that C1 is replaced by C2.

Table 75: Compounds of formula (I), wherein Cy¹ and Cy² and R¹ to R⁴ areas shown in Table 38, with the exception that C1 is replaced by C2.

Table 76: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 2, with the exception that C1 is replaced by C3.

Table 77: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 3, with the exception that C1 is replaced by C3.

Table 78: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 4, with the exception that C1 is replaced by C3.

Table 79: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 5, with the exception that C1 is replaced by C3.

Table 80: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 6, with the exception that C1 is replaced by C3.

Table 81: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 7, with the exception that C1 is replaced by C3.

Table 82: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 8, with the exception that C1 is replaced by C3.

Table 83: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 9, with the exception that C1 is replaced by C3.

Table 84: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 10, with the exception that C1 is replaced by C3.

Table 85: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 11, with the exception that C1 is replaced by C3.

Table 86: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 12, with the exception that C1 is replaced by C3.

Table 87: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 13, with the exception that C1 is replaced by C3.

Table 88: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 14, with the exception that C1 is replaced by C3.

Table 89: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 15, with the exception that C1 is replaced by C3.

Table 90: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 16, with the exception that C1 is replaced by C3.

Table 91: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 17, with the exception that C1 is replaced by C3.

Table 92: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 18, with the exception that C1 is replaced by C3.

Table 93: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 19, with the exception that C1 is replaced by C3.

Table 94: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 20, with the exception that C1 is replaced by C3.

Table 95: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 21, with the exception that C1 is replaced by C3.

Table 96: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 22, with the exception that C1 is replaced by C3.

Table 97: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 23, with the exception that C1 is replaced by C3.

Table 98: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 24, with the exception that C1 is replaced by C3.

Table 99: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4 areas shown in Table 25, with the exception that C1 is replaced by C3.

Table 100: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C3.

Table 101: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C3.

Table 102: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C3.

Table 103: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C3.

Table 104: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C3.

Table 105: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C3.

Table 106: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C3.

Table 107: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C3.

Table 108: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C3.

Table 109: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C3.

Table 110: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C3.

Table 111: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C3.

Table 112: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C3.

Table 113: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C4.

Table 114: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C4.

Table 115: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C4.

Table 116: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C4.

Table 117: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C4.

Table 118: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C4.

Table 119: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C4.

Table 120: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C4.

Table 121: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C4.

Table 122: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C4.

Table 123: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C4.

Table 124: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C4.

Table 125: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C4.

Table 126: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C4.

Table 127: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C4.

Table 128: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C4.

Table 129: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C4.

Table 130: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C4.

Table 131: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C4.

Table 132: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C4.

Table 133: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C4.

Table 134: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C4.

Table 135: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C4.

Table 136: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C4.

Table 137: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C4.

Table 138: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C4.

Table 139: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C4.

Table 140: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C4.

Table 141: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C4.

Table 142: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C4.

Table 143: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C4.

Table 144: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C4.

Table 145: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C4.

Table 146: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C4.

Table 147: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C4.

Table 148: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C4.

Table 149: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C4.

Table 150: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C5.

Table 151: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C5.

Table 152: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C5.

Table 153: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C5.

Table 154: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C5.

Table 155: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C5.

Table 156: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C5.

Table 157: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C5.

Table 158: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C5.

Table 159: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C5.

Table 160: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C5.

Table 161: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C5.

Table 162: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C5.

Table 163: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C5.

Table 164: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C5.

Table 165: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C5.

Table 166: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C5.

Table 167: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C5.

Table 168: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C5.

Table 169: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C5.

Table 170: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C5.

Table 171: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C5.

Table 172: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C5.

Table 173: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C5.

Table 174: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C5.

Table 175: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C5.

Table 176: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C5.

Table 177: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C5.

Table 178: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C5.

Table 179: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C5.

Table 180: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C5.

Table 181: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C5.

Table 182: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C5.

Table 183: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C5.

Table 184: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C5.

Table 185: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C5.

Table 186: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C5.

Table 187: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C6.

Table 188: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C6.

Table 189: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C6.

Table 190: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C6.

Table 191: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C6.

Table 192: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C6.

Table 193: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C6.

Table 194: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C6.

Table 195: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C6.

Table 196: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C6.

Table 197: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C6.

Table 198: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C6.

Table 199: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C6.

Table 200: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C6.

Table 201: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C6.

Table 202: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C6.

Table 203: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C6.

Table 204: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C6.

Table 205: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C6.

Table 206: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C6.

Table 207: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C6.

Table 208: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C6.

Table 209: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C6.

Table 210: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C6.

Table 211: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C6.

Table 212: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C6.

Table 213: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C6.

Table 214: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C6.

Table 215: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C6.

Table 216: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C6.

Table 217: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C6.

Table 218: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C6.

Table 219: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C6.

Table 220: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C6.

Table 221: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C6.

Table 222: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C6.

Table 223: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C6.

Table 224: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C7.

Table 225: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C7.

Table 226: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C7.

Table 227: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C7.

Table 228: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C7.

Table 229: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C7.

Table 230: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C7.

Table 231: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C7.

Table 232: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C7.

Table 233: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C7.

Table 234: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C7.

Table 235: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C7.

Table 236: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C7.

Table 237: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C7.

Table 238: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C7.

Table 239: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C7.

Table 240: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C7.

Table 241: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C7.

Table 242: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C7.

Table 243: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C7.

Table 244: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C7.

Table 245: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C7.

Table 246: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C7.

Table 247: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C7.

Table 248: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C7.

Table 249: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C7.

Table 250: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C7.

Table 251: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C7.

Table 252: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C7.

Table 253: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C7.

Table 254: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C7.

Table 255: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C7.

Table 256: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C7.

Table 257: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C7.

Table 258: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C7.

Table 259: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C7.

Table 260: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C7.

Table 261: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C8.

Table 262: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C8.

Table 263: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C8.

Table 264: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C8.

Table 265: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C8.

Table 266: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C8.

Table 267: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C8.

Table 268: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C8.

Table 269: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C8.

Table 270: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C8.

Table 271: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C8.

Table 272: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C8.

Table 273: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C8.

Table 274: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C8.

Table 275: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C8.

Table 276: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C8.

Table 277: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C8.

Table 278: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C8.

Table 279: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C8.

Table 280: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C8.

Table 281: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C8.

Table 282: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C8.

Table 283: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C8.

Table 284: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C8.

Table 285: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C8.

Table 286: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C8.

Table 287: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C8.

Table 288: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C8.

Table 289: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C8.

Table 290: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C8.

Table 291: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C8.

Table 292: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C8.

Table 293: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C8.

Table 294: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C8.

Table 295: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C8.

Table 296: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C8.

Table 297: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C8.

Table 298: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C9.

Table 299: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C9.

Table 300: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C9.

Table 301: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C9.

Table 302: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C9.

Table 303: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C9.

Table 304: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C9.

Table 305: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C9.

Table 306: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C9.

Table 307: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C9.

Table 308: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C9.

Table 309: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C9.

Table 310: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C9.

Table 311: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C9.

Table 312: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C9.

Table 313: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C9.

Table 314: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C9.

Table 315: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C9.

Table 316: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C9.

Table 317: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C9.

Table 318: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C9.

Table 319: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C9.

Table 320: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C9.

Table 321: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C9.

Table 322: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C9.

Table 323: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C9.

Table 324: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C9.

Table 325: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C9.

Table 326: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C9.

Table 327: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C9.

Table 328: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C9.

Table 329: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C9.

Table 330: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C9.

Table 331: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C9.

Table 332: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C9.

Table 333: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C9.

Table 334: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C9.

Table 335: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C10.

Table 336: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C10.

Table 337: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C10.

Table 338: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C10.

Table 339: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C10.

Table 340: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C10.

Table 341: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C10.

Table 342: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C10.

Table 343: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C10.

Table 344: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C10.

Table 345: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C10.

Table 346: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C10.

Table 347: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C10.

Table 348: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C10.

Table 349: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C10.

Table 350: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C10.

Table 351: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C10.

Table 352: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C10.

Table 353: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C10.

Table 354: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C10.

Table 355: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C10.

Table 356: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C10.

Table 357: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C10.

Table 358: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C10.

Table 359: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C10.

Table 360: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C10.

Table 361: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C10.

Table 362: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C10.

Table 363: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C10.

Table 364: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C10.

Table 365: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C10.

Table 366: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C10.

Table 367: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C10.

Table 368: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C10.

Table 369: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C10.

Table 370: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C10.

Table 371: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C10.

Table 372: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C11.

Table 373: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C11.

Table 374: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C11.

Table 375: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C11.

Table 376: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C11.

Table 377: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C11.

Table 378: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C11.

Table 379: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C11.

Table 380: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C11.

Table 381: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C11.

Table 382: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C11.

Table 383: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C11.

Table 384: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C11.

Table 385: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C11.

Table 386: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C11.

Table 387: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C11.

Table 388: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C11.

Table 389: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C11.

Table 390: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C11.

Table 391: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C11.

Table 392: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C11.

Table 393: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C11.

Table 394: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C11.

Table 395: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C11.

Table 396: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C11.

Table 397: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C11.

Table 398: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C11.

Table 399: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C11.

Table 400: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C11.

Table 401: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C11.

Table 402: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C11.

Table 403: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C11.

Table 404: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C11.

Table 405: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C11.

Table 406: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C11.

Table 407: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C11.

Table 408: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C11.

Table 409: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C12.

Table 410: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C12.

Table 411: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C12.

Table 412: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C12.

Table 413: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C12.

Table 414: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C12.

Table 415: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C12.

Table 416: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C12.

Table 417: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C12.

Table 418: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C12.

Table 419: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C12.

Table 420: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C12.

Table 421: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C12.

Table 422: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C12.

Table 423: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C12.

Table 424: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C12.

Table 425: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C12.

Table 426: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C12.

Table 427: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C12.

Table 428: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C12.

Table 429: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C12.

Table 430: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C12.

Table 431: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C12.

Table 432: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C12.

Table 433: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C12.

Table 434: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C12.

Table 435: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C12.

Table 436: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C12.

Table 437: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C12.

Table 438: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C12.

Table 439: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C12.

Table 440: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C12.

Table 441: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C12.

Table 442: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C12.

Table 443: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C12.

Table 444: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C12.

Table 445: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C12.

Table 446: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C13.

Table 447: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C13.

Table 448: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C13.

Table 449: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C13.

Table 450: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C13.

Table 451: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C13.

Table 452: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C13.

Table 453: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C13.

Table 454: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C13.

Table 455: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C13.

Table 456: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C13.

Table 457: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C13.

Table 458: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C13.

Table 459: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C13.

Table 460: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C13.

Table 461: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C13.

Table 462: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C13.

Table 463: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C13.

Table 464: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C13.

Table 465: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C13.

Table 466: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C13.

Table 467: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C13.

Table 468: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C13.

Table 469: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C13.

Table 470: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C13.

Table 471: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C13.

Table 472: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C13.

Table 473: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C13.

Table 474: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C13.

Table 475: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C13.

Table 476: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C13.

Table 477: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C13.

Table 478: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C13.

Table 479: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C13.

Table 480: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C13.

Table 481: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C13.

Table 482: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C13.

Table 483: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C14.

Table 484: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C14.

Table 485: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C14.

Table 486: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C14.

Table 487: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C14.

Table 488: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C14.

Table 489: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C14.

Table 490: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C14.

Table 491: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C14.

Table 492: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C14.

Table 493: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C14.

Table 494: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C14.

Table 495: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C14.

Table 496: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C14.

Table 497: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C14.

Table 498: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C14.

Table 499: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C14.

Table 500: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C14.

Table 501: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C14.

Table 502: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C14.

Table 503: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C14.

Table 504: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C14.

Table 505: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C14.

Table 506: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C14.

Table 507: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C14.

Table 508: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C14.

Table 509: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C14.

Table 510: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C14.

Table 511: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C14.

Table 512: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C14.

Table 513: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C14.

Table 514: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C14.

Table 515: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C14.

Table 516: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C14.

Table 517: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C14.

Table 518: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C14.

Table 519: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C14.

Table 520: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C15.

Table 521: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C15.

Table 522: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C15.

Table 523: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C15.

Table 524: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C15.

Table 525: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C15.

Table 526: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C15.

Table 527: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C15.

Table 528: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C15.

Table 529: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C15.

Table 530: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C15.

Table 531: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C15.

Table 532: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C15.

Table 533: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C15.

Table 534: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C15.

Table 535: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C15.

Table 536: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C15.

Table 537: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C15.

Table 538: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C15.

Table 539: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C15.

Table 540: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C15.

Table 541: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C15.

Table 542: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C15.

Table 543: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C15.

Table 544: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C15.

Table 545: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C15.

Table 546: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C15.

Table 547: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C15.

Table 548: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C15.

Table 549: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C15.

Table 550: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C15.

Table 551: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C15.

Table 552: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C15.

Table 553: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C15.

Table 554: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C15.

Table 555: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C15.

Table 556: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C15.

Table 557: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C16.

Table 558: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C16.

Table 559: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C16.

Table 560: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C16.

Table 561: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C16.

Table 562: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C16.

Table 563: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C16.

Table 564: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C16.

Table 565: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C16.

Table 566: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C16.

Table 567: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C16.

Table 568: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C16.

Table 569: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C16.

Table 570: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C16.

Table 571: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C16.

Table 572: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C16.

Table 573: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C16.

Table 574: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C16.

Table 575: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C16.

Table 576: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C16.

Table 577: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C16.

Table 578: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C16.

Table 579: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C16.

Table 580: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C16.

Table 581: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C16.

Table 582: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C16.

Table 583: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C16.

Table 584: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C16.

Table 585: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C16.

Table 586: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C16.

Table 587: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C16.

Table 588: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C16.

Table 589: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C16.

Table 590: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C16.

Table 591: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C16.

Table 592: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C16.

Table 593: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C16.

Table 594: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C17.

Table 595: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C17.

Table 596: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C17.

Table 597: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C17.

Table 598: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C17.

Table 599: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C17.

Table 600: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C17.

Table 601: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C17.

Table 602: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C17.

Table 603: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C17.

Table 604: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C17.

Table 605: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C17.

Table 606: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C17.

Table 607: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C17.

Table 608: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C17.

Table 609: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C17.

Table 610: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C17.

Table 611: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C17.

Table 612: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C17.

Table 613: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C17.

Table 614: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C17.

Table 615: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C17.

Table 616: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C17.

Table 617: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C17.

Table 618: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C17.

Table 619: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C17.

Table 620: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C17.

Table 621: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C17.

Table 622: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C17.

Table 623: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C17.

Table 624: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C17.

Table 625: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C17.

Table 626: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C17.

Table 627: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C17.

Table 628: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C17.

Table 629: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C17.

Table 630: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C17.

Table 631: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C18.

Table 632: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C18.

Table 633: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C18.

Table 634: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C18.

Table 635: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C18.

Table 636: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C18.

Table 637: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C18.

Table 638: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C18.

Table 639: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C18.

Table 640: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C18.

Table 641: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C18.

Table 642: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C18.

Table 643: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C18.

Table 644: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C18.

Table 645: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C18.

Table 646: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C18.

Table 647: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C18.

Table 648: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C18.

Table 649: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C18.

Table 650: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C18.

Table 651: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C18.

Table 652: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C18.

Table 653: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C18.

Table 654: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C18.

Table 655: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C18.

Table 656: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C18.

Table 657: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C18.

Table 658: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C18.

Table 659: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C18.

Table 660: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C18.

Table 661: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C18.

Table 662: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C18.

Table 663: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C18.

Table 664: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C18.

Table 665: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C18.

Table 666: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C18.

Table 667: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C18.

Table 668: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C19.

Table 669: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C19.

Table 670: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C19.

Table 671: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C19.

Table 672: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C19.

Table 673: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C19.

Table 674: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C19.

Table 675: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C19.

Table 676: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C19.

Table 677: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C19.

Table 678: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C19.

Table 679: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C19.

Table 680: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C19.

Table 681: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C19.

Table 682: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C19.

Table 683: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C19.

Table 684: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C19.

Table 685: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C19.

Table 686: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C19.

Table 687: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C19.

Table 688: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C19.

Table 689: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C19.

Table 690: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C19.

Table 691: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C19.

Table 692: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C19.

Table 693: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C19.

Table 694: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C19.

Table 695: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C19.

Table 696: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C19.

Table 697: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C19.

Table 698: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C19.

Table 699: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C19.

Table 700: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C19.

Table 701: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C19.

Table 702: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C19.

Table 703: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C19.

Table 704: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C19.

Table 705: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C20.

Table 706: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C20.

Table 707: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C20.

Table 708: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C20.

Table 709: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C20.

Table 710: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C20.

Table 711: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C20.

Table 712: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C20.

Table 713: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C20.

Table 714: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C20.

Table 715: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C20.

Table 716: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C20.

Table 717: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C20.

Table 718: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C20.

Table 719: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C20.

Table 720: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C20.

Table 721: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C20.

Table 722: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C20.

Table 723: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C20.

Table 724: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C20.

Table 725: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C20.

Table 726: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C20.

Table 727: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C20.

Table 728: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C20.

Table 729: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C20.

Table 730: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C20.

Table 731: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C20.

Table 732: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C20.

Table 733: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C20.

Table 734: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C20.

Table 735: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C20.

Table 736: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C20.

Table 737: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C20.

Table 738: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C20.

Table 739: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C20.

Table 740: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C20.

Table 741: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C20.

Table 742: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C21.

Table 743: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C21.

Table 744: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C21.

Table 745: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C21.

Table 746: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C21.

Table 747: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C21.

Table 748: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C21.

Table 749: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C21.

Table 750: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C21.

Table 751: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C21.

Table 752: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C21.

Table 753: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C21.

Table 754: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C21.

Table 755: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C21.

Table 756: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C21.

Table 757: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C21.

Table 758: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C21.

Table 759: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C21.

Table 760: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C21.

Table 761: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C21.

Table 762: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C21.

Table 763: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C21.

Table 764: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C21.

Table 765: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C21.

Table 766: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C21.

Table 767: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C21.

Table 768: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C21.

Table 769: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C21.

Table 770: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C21.

Table 771: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C21.

Table 772: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C21.

Table 773: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C21.

Table 774: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C21.

Table 775: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C21.

Table 776: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C21.

Table 777: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C21.

Table 778: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C21.

Table 779: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C22.

Table 780: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C22.

Table 781: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C22.

Table 782: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C22.

Table 783: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C22.

Table 784: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C22.

Table 785: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C22.

Table 786: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C22.

Table 787: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C22.

Table 788: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C22.

Table 789: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C22.

Table 790: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C22.

Table 791: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C22.

Table 792: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C22.

Table 793: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C22.

Table 794: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C22.

Table 795: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C22.

Table 796: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C22.

Table 797: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C22.

Table 798: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C22.

Table 799: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C22.

Table 800: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C22.

Table 801: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C22.

Table 802: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C22.

Table 803: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C22.

Table 804: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C22.

Table 805: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C22.

Table 806: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C22.

Table 807: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C22.

Table 808: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C22.

Table 809: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C22.

Table 810: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C22.

Table 811: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C22.

Table 812: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C22.

Table 813: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C22.

Table 814: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C22.

Table 815: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C22.

Table 816: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C23.

Table 817: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C23.

Table 818: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C23.

Table 819: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C23.

Table 820: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C23.

Table 821: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C23.

Table 822: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C23.

Table 823: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C23.

Table 824: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C23.

Table 825: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C23.

Table 826: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C23.

Table 827: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C23.

Table 828: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C23.

Table 829: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C23.

Table 830: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C23.

Table 831: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C23.

Table 832: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C23.

Table 833: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C23.

Table 834: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C23.

Table 835: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C23.

Table 836: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C23.

Table 837: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C23.

Table 838: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C23.

Table 839: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C23.

Table 840: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C23.

Table 841: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C23.

Table 842: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C23.

Table 843: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C23.

Table 844: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C23.

Table 845: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C23.

Table 846: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C23.

Table 847: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C23.

Table 848: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C23.

Table 849: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C23.

Table 850: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C23.

Table 851: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C23.

Table 852: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C23.

Table 853: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C24.

Table 854: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C24.

Table 855: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C24.

Table 856: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C24.

Table 857: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C24.

Table 858: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C24.

Table 859: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C24.

Table 860: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C24.

Table 861: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C24.

Table 862: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C24.

Table 863: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C24.

Table 864: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C24.

Table 865: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C24.

Table 866: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C24.

Table 867: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C24.

Table 868: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C24.

Table 869: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C24.

Table 870: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C24.

Table 871: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C24.

Table 872: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C24.

Table 873: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C24.

Table 874: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C24.

Table 875: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C24.

Table 876: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C24.

Table 877: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C24.

Table 878: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C24.

Table 879: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C24.

Table 880: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C24.

Table 881: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C24.

Table 882: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C24.

Table 883: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C24.

Table 884: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C24.

Table 885: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C24.

Table 886: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C24.

Table 887: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C24.

Table 888: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C24.

Table 889: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C24.

Table 890: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C25.

Table 891: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C25.

Table 892: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C25.

Table 893: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C25.

Table 894: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C25.

Table 895: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C25.

Table 896: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C25.

Table 897: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C25.

Table 898: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C25.

Table 899: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C25.

Table 900: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C25.

Table 901: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C25.

Table 902: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C25.

Table 903: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C25.

Table 904: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C25.

Table 905: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C25.

Table 906: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C25.

Table 907: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C25.

Table 908: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C25.

Table 909: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C25.

Table 910: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C25.

Table 911: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C25.

Table 912: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C25.

Table 913: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C25.

Table 914: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C25.

Table 915: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C25.

Table 916: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C25.

Table 917: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C25.

Table 918: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C25.

Table 919: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C25.

Table 920: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C25.

Table 921: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C25.

Table 922: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C25.

Table 923: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C25.

Table 924: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C25.

Table 925: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C25.

Table 926: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C25.

Table 927: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C26.

Table 928: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C26.

Table 929: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C26.

Table 930: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C26.

Table 931: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C26.

Table 932: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C26.

Table 933: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C26.

Table 934: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C26.

Table 935: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C26.

Table 936: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C26.

Table 937: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C26.

Table 938: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C26.

Table 939: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C26.

Table 940: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C26.

Table 941: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C26.

Table 942: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C26.

Table 943: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C26.

Table 944: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C26.

Table 945: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C26.

Table 946: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C26.

Table 947: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C26.

Table 948: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C26.

Table 949: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C26.

Table 950: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C26.

Table 951: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C26.

Table 952: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C26.

Table 953: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C26.

Table 954: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C26.

Table 955: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C26.

Table 956: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C26.

Table 957: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C26.

Table 958: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C26.

Table 959: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C26.

Table 960: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C26.

Table 961: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C26.

Table 962: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C26.

Table 963: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C26.

Table 964: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C27.

Table 965: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C27.

Table 966: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C27.

Table 967: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C27.

Table 968: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C27.

Table 969: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C27.

Table 970: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C27.

Table 971: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C27.

Table 972: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C27.

Table 973: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C27.

Table 974: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C27.

Table 975: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C27.

Table 976: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C27.

Table 977: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C27.

Table 978: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C27.

Table 979: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C27.

Table 980: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C27.

Table 981: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C27.

Table 982: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C27.

Table 983: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C27.

Table 984: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C27.

Table 985: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C27.

Table 986: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C27.

Table 987: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C27.

Table 988: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C27.

Table 989: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C27.

Table 990: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C27.

Table 991: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C27.

Table 992: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C27.

Table 993: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C27.

Table 994: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C27.

Table 995: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C27.

Table 996: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C27.

Table 997: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C27.

Table 998: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C27.

Table 999: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C27.

Table 1000: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C27.

Table 1001: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 2, with the exception that C1 is replaced by C28.

Table 1002: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 3, with the exception that C1 is replaced by C28.

Table 1003: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 4, with the exception that C1 is replaced by C28.

Table 1004: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 5, with the exception that C1 is replaced by C28.

Table 1005: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 6, with the exception that C1 is replaced by C28.

Table 1006: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 7, with the exception that C1 is replaced by C28.

Table 1007: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 8, with the exception that C1 is replaced by C28.

Table 1008: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 9, with the exception that C1 is replaced by C28.

Table 1009: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 10, with the exception that C1 is replaced by C28.

Table 1010: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 11, with the exception that C1 is replaced by C28.

Table 1011: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 12, with the exception that C1 is replaced by C28.

Table 1012: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 13, with the exception that C1 is replaced by C28.

Table 1013: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 14, with the exception that C1 is replaced by C28.

Table 1014: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 15, with the exception that C1 is replaced by C28.

Table 1015: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 16, with the exception that C1 is replaced by C28.

Table 1016: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 17, with the exception that C1 is replaced by C28.

Table 1017: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 18, with the exception that C1 is replaced by C28.

Table 1018: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 19, with the exception that C1 is replaced by C28.

Table 1019: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 20, with the exception that C1 is replaced by C28.

Table 1020: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 21, with the exception that C1 is replaced by C28.

Table 1021: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 22, with the exception that C1 is replaced by C28.

Table 1022: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 23, with the exception that C1 is replaced by C28.

Table 1023: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 24, with the exception that C1 is replaced by C28.

Table 1024: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 25, with the exception that C1 is replaced by C28.

Table 1025: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 26, with the exception that C1 is replaced by C28.

Table 1026: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 27, with the exception that C1 is replaced by C28.

Table 1027: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 28, with the exception that C1 is replaced by C28.

Table 1028: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 29, with the exception that C1 is replaced by C28.

Table 1029: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 30, with the exception that C1 is replaced by C28.

Table 1030: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 31, with the exception that C1 is replaced by C28.

Table 1031: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 32, with the exception that C1 is replaced by C28.

Table 1032: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 33, with the exception that C1 is replaced by C28.

Table 1033: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 34, with the exception that C1 is replaced by C28.

Table 1034: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 35, with the exception that C1 is replaced by C28.

Table 1035: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 36, with the exception that C1 is replaced by C28.

Table 1036: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 37, with the exception that C1 is replaced by C28.

Table 1037: Compounds of formula (I), wherein Cy1 and Cy2 and R1 to R4are as shown in Table 38, with the exception that C1 is replaced by C28.

Surprisingly, it has been found that substitution of the alkyl groupsR¹, R², R³ and R⁴, which are 2-methylpropyl groups in the parent cyclicdepsipeptide PF1022A and also in emodepside, with certain groupsdescribed herein improve the metabolic stability of the compounds andalso improves the activity of the compounds against endoparasites and insome embodiments against ectoparasites. In some cases, the compounds ofthe invention may exhibit lower toxicity in mammals. Furthermore, it hasbeen surprisingly found that substitution of the compounds of formula(I) with certain Cy¹ and/or Cy² groups described herein alsosignificantly improves the metabolic stability of the compounds of theinvention compared with PF1022A and emodepside. Thus, the compounds ofthe invention where the groups Cy¹ and/or Cy² and at least one of R¹,R², R³ and R⁴ are substituted with certain substituents described hereinhave been found to have significantly improved metabolic stability andequal or significantly improved efficacy against endoparasitesincluding, but not limited to, Dirofilaria immitis microfilaria and/orL3 and L4 larvae and/or Haemonchus contortus larvae. The compounds ofthe invention are also active against hookworms, whipworms androundworms of the digestive tract of animals. In some embodiments, thecompounds of formula (I) with certain substituents will also exhibitimproved activity against ectoparasites.

In some embodiments, certain compounds of the invention where at leastone of R¹ to R⁴ is an optionally substituted 3- to 6-memberedcarbocyclic or 3- to 6-membered heterocyclic ring or C₁-C₃ alkyl orC₁-C₃ haloalkyl, wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl issubstituted by an optionally substituted 3- to 8-membered carbocyclic or3- to 8-membered heterocyclic ring, or may exhibit improved toxicityprofiles compared with compounds having acyclic alkyl groups at thesepositions. In other embodiments of the invention wherein one or more ofR¹ to R⁴ together with the corresponding R^(1′) to R^(4′) form a2-6-membered carbon chain to form a ring the cyclic depsipeptides mayexhibit improved toxicity profiles compared with compounds havingacyclic alkyl groups at these positions.

It has also been surprisingly found that the spatial order ofsubstitution of R¹ to R⁴ also has a significant impact on the activityof the compounds. For example it has been found that when thenaturally-occurring 2-methylpropyl groups at the positions identified asR¹ and R³ in the compound of formula (I) are modified the activity ofthe compounds is significantly improved over compounds where the2-methylpropyl groups at the positions R² and R⁴ are substituted.

The influence of certain substituents on the naturally-occurring2-methylpropyl group of the N-methyl leucine residues of PF1022A,corresponding to one or more of R¹, R², R³ and R⁴ in formula (I), isalso surprising. Thus, substitution of one or more of the 2-methylpropylat R¹, R², R³ and R⁴ with fluoro has been found to significantly improvethe activity of the compounds of formula (I) on the motility ofHaemonchus contortus larvae and Dirofilaria immitis microfilaria invitro compared with unsubstituted compounds (e.g. PF1022A or analogswhere Cy¹ and/or Cy² are substituted phenyl but R¹ to R⁴ are2-methylpropyl) or compounds in which the naturally-occurring2-methylpropyl groups are substituted with a methyl group. In addition,the substitution of the 2-methylpropyl groups at R¹ and R³ groups withfluoro has been found to result in significantly improved activityagainst H. contortus and D. immitis microfilaria larvae compared withcompounds substituted with fluoro at R² and R⁴ or other combinations. Inaddition, in some embodiments the inclusion in variables R¹ to R⁴ of atleast one optionally substituted 3- to 6-membered carbocyclic or 3- to6-membered heterocyclic ring or a C₁-C₃ alkyl or C₁-C₃ haloalkyl,wherein the C₁-C₃ alkyl or C₁-C₃ haloalkyl is substituted by anoptionally substituted 3- to 8-membered carbocyclic or 3- to 8-memberedheterocyclic ring or wherein one or more of R¹ to R⁴ together with thecorresponding R^(1′) to R^(4′) form a 2-6-membered carbon chain to forma ring may improve the safety profile and/or the metabolic stability ofthe compounds thereby increasing the therapeutic window. It is apparentthat the type of substitution in groups R¹, R², R³ and R⁴ as well aswhich of R¹, R², R³ and R⁴ are substituted have a significant influenceon the activity, stability and safety of the compounds.

Scherkenbeck et al. (Bioorg. Med. Chem. Lett. 8 (1998), 1035-1040)described that the modification of the N-methyl leucine residues for aseries of related N-methylated amino acids such as isoleucine, valine,norvaline, alanine and phenylalanine resulted in nearly complete loss ofanthelmintic activity following oral administration in sheep.Furthermore, the publication reported that modification of half of theN-methyl leucine residues with either methyl or n-propyl side chainsalso surprisingly resulted in significantly reduced activity. It wasconcluded that the (L)-N-methyl leucine residues in the cyclicdepsipeptide PF1022A were a critical part of the pharmacophore andessential for in vivo activity.

Thus, it is surprising and unexpected that modification of the groups R¹to R⁴ in the compound of formula (I), which correspond to the N-methylleucine residues in PF1022A or emodepside, result in enhanced metabolicstability and/or lower toxicity and/or improved activity compared withthe compounds containing unmodified N-methyl leucine residues. It isalso very surprising and unexpected that the compounds of formula (I) inwhich the alkyl groups represented by R¹ and R³ are substituted withcertain groups described herein exhibit significantly improved efficacyagainst endoparasites compared to compounds that are substituted withthe same groups at R² and R⁴ or in other combinations. In addition, theinclusion of certain substituents described herein in groups R¹ to R⁴and Cy¹ and Cy² result in improved metabolic stability and lowertoxicity compared with unsubstituted compounds. It follows that acombination of the substitution at Cy¹ and Cy² and R¹ to R⁴ in thecompounds of formula (I) results in significantly improved activityagainst endoparasites and improved metabolic stability.

Furthermore, the substitution of the naturally-occurring 2-methylpropylgroups with certain substituents, including fluoro and methyl, has beenfound to improve the in vitro permeability and the bioavailability ofthe compounds (see Method C in Examples). For example, compounds offormula (I) wherein Cy¹ and Cy² are either both unsubstituted phenyl orp-fluorophenyl groups and R² and R⁴, respectively, are fluoro were foundto have significantly improved permeability compared with the compoundswhere R² and R⁴ are unsubstituted 2-methylpropyl. Further, compoundswhere Cy¹ and Cy² are p-morpholino phenyl and R² and R⁴ are methyl werefound to have significantly improved permeability compared withemodepside (R² and R⁴═H).

The characteristics described above for the compounds of formula (I) areexpected to result in compounds with superior antiparasitic efficacyagainst endoparasites and ectoparasites in or on animals.

Stereoisomers and Polymorphic Forms

It will be appreciated by those of skill in the art that the compoundsof the invention may exist and be isolated as optically active andracemic forms. Compounds having one or more chiral centers, includingthat at a sulfur atom, may be present as single enantiomers ordiastereomers or as mixtures of enantiomers and/or diastereomers. Forexample, it is well known in the art that sulfoxide compounds may beoptically active and may exist as single enantiomers or racemicmixtures. In addition, compounds of the invention may include one ormore chiral centers, which results in a theoretical number of opticallyactive isomers. Where compounds of the invention include n chiralcenters, the compounds may comprise up to 2^(n) optical isomers. Thepresent invention encompasses the specific enantiomers or diastereomersof each compound as well as mixtures of different enantiomers and/ordiastereomers of the compounds of the invention that possess the usefulproperties described herein. The optically active forms can be preparedby, for example, resolution of the racemic forms by selectivecrystallization techniques, by synthesis from optically activeprecursors, by chiral synthesis, by chromatographic separation using achiral stationary phase or by enzymatic resolution.

The compounds of present invention may also be present in differentsolid forms such as different crystalline forms or in the form of anamorphous solid. The present invention encompasses different crystallineforms as well as amorphous forms of the inventive compounds.

In addition, the compounds of the invention may exist as hydrates orsolvates, in which a certain stoichiometric amount of water or a solventis associated with the molecule in the crystalline form. The hydratesand solvates of the compounds of formula (I) are also the subject of theinvention.

Salts

In addition to the neutral compounds of formula (I), salt forms of thecompounds are also active against parasites. The terms “veterinarilyacceptable salt” and “pharmaceutically acceptable salt” are usedthroughout the specification to describe any salts of the compounds thatare acceptable for administration for veterinary applications, and whichprovides the active compound upon administration.

In cases where compounds are sufficiently basic or acidic to form stablenon-toxic acid or base salts, the compounds may be in the form of aveterinarily, pharmaceutically or agriculturally acceptable salt.Veterinarily acceptable salts include those derived from veterinarily oragriculturally acceptable inorganic or organic bases and acids. Suitablesalts include those comprising alkali metals such as lithium, sodium orpotassium, alkaline earth metals such as calcium, magnesium and barium.Salts comprising transition metals including, but not limited to,manganese, copper, zinc and iron are also suitable. In addition, saltscomprising ammonium cations (NH₄ ⁺) as well as substituted ammoniumcations, in which one or more of the hydrogen atoms are replaced byalkyl or aryl groups are encompassed by the invention.

Salts derived from inorganic acids including, but not limited to,hydrohalide acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid,phosphoric acid, and the like are particularly suitable. Suitableinorganic salts also include, but not limited to, bicarbonate, andcarbonate salts. In some embodiments, examples of veterinarily andagriculturally acceptable salts are organic acid addition salts formedwith organic acids including, but not limited to, maleate, dimaleate,fumarate, tosylate, methanesulfonate, acetate, citrate, malonate,tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, andα-glycerophosphate. Of course, other acceptable organic acids may beused.

Alkali metal (for example, sodium, potassium or lithium) or alkalineearth metal (for example calcium) salts of the compounds can also bemade by reacting a sufficiently acidic residue on the compounds with ahydroxide of the alkali metal or alkaline earth metal.

Veterinarily acceptable salts may be obtained using standard procedureswell known in the art, for example by reacting a sufficiently basiccompound such as an amine with a suitably acid functional group presentin the compound, or by reacting a suitable acid with a suitably basicfunctional group on the compound of the invention.

Processes for the Preparation of Compounds of Formula (I):

The compounds of formula (I) may be prepared by processes adapted fromthose described in U.S. Pat. Nos. 5,514,773; 5,747,448; 5,874,530;5,856,436; 6,033,879; 5,763,221; 6,329,338, 5,116,815; 6,468,966;6,369,028; 5,777,075; and 5,646,244, all which are hereby incorporatedby reference in their entirety. In addition, various synthetic methodsfor cyclic depsipeptides have been reported in the chemical literature(see Luttenberg et al., Tetrahedron 68 (2012), 2068-2073; Byung H. Lee,Tetrahedron Letters, 1997, 38 (5), 757-760; Scherkenbeck et al., Lettersin Organic Chemistry, 2016, 13, 441-445; Eur. J. Org. Chem., 2012,1546-1553; Biosci. Biotech. Biochem., 1994, 58(6), 1193-1194; andScherkenbeck et al., Tetrahedron, 1995, 51(31), 8459-8470) It will beunderstood by those skilled in the art that certain functional groups inthe compounds and intermediates may be unprotected or protected bysuitable protecting groups, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Inc., 4^(th) edition 2006.Further, it will be apparent to those skilled in the art that thecompounds and intermediates may be isolated by standard aqueous work-upconditions and optionally purified. For example, the compounds orintermediates may be purified by chromatographic methods or crystallizedto yield the desired product in suitable purity.

In one embodiment, the compounds of formula (I) where R¹, R^(1′), R²,R^(2′), R³, R^(3′), R⁴, R^(4′), R^(a), R^(b), Cy¹ and Cy² are as definedabove, R′, R″, R′″ and R″″ are methyl are prepared according to thegeneral process described in Scheme 1 below:

In scheme 1, P₁ and P₂ are amine and carboxylic acid protecting groups,respectively, commonly used in the art (see, for example, Greene et al.Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 4thedition 2006) and R¹, R², R³, R⁴, R^(a), R^(b), Cy¹ and Cy² are asdefined above.

Furthermore, the coupling of amines with carboxylic acids to form amidesis well known in the art and standard reagents may be used in thecoupling of a fragment with an unprotected amine with a second fragmenthaving a free carboxylic acid group (see for example, Peptide Synthesisby Miklos Bodanszky and Miguel Ondetti, Interscience Publishers, 1966;Amino Acid and Peptide Synthesis, 2^(nd) Ed. By John Jones, OxfordUniversity Press, 2002). The compounds may be prepared by solution phasesynthesis or using solid-phase synthesis with polymeric supports. Forexample, the formation of amide bonds may be mediated by activatingreagents such as carbodiimide reagents (e.g. dicyclohexyldiimide,diisopropyldiimide and(N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide.HCl) in combination withadditives such as N-hydroxybenzotriazole (HOBt) and the like. Inaddition, the formation of amide bonds in the synthesis may beaccomplished by using phosphonium reagents such as BOP(Benzotriazol-1-yloxy-tris (dimethylamino)-phosphoniumhexafluorophosphate), PyBOP(Benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate),PyBrOP (Bromo-tripyrrolidino-phosphonium hexa-fluorophosphate) and thelike. Other useful reagents for forming the amide bonds of the compoundsof the invention are the so called aminium/uronium-imonium reagents suchas TBTU/HBTU (2-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumtetrafluoroborate/hexafluorophosphate), HATU(2-(7-Aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumhexafluorophosphate) and the like. These reagents and the methodsemploying these reagents for the preparation of amide bonds are wellknown in the art.

Veterinary Compositions:

The compounds of formula (I) and compositions comprising the compoundsare useful for the prevention and treatment of parasiticinfestations/infections in animals. The compositions of the inventioncomprise an effective amount of at least one cyclic depsipeptidecompound of formula (I), or a veterinarily acceptable salt thereof, incombination with a veterinarily acceptable carrier or diluent andoptionally other non-active excipients. The compositions may be in avariety of solid and liquid forms which are suitable for various formsof application or administration to an animal. For example, theveterinary compositions comprising the inventive compounds may be informulations suitable for oral administration, injectableadministration, including subcutaneous and parenteral administration,and topical administration (e.g. spot-on or pour-on), dermal orsubdermal administration. The formulations are intended to beadministered to an animal including, but not limited to, mammals, birdsand fish. Examples of mammals include but are not limited to humans,cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, catsand other livestock or domestic mammals. Examples of birds includeturkeys, chickens, ostriches and other livestock or domestic birds. Theuse of the compounds of formula (I) to protect companion animals such asdogs and cats from endoparasites is particularly useful.

The compositions of the invention may be in a form suitable for oral use(see, e.g., U.S. Pat. No. 4,564,631, which is hereby incorporated byreference in its entirety), dietary supplements, troches, lozenges,chewables, tablets, hard or soft capsules, bolus, emulsions, aqueous oroily suspensions, aqueous or oily solutions, oral drench formulations,dispersible powders or granules, premixes, syrups or elixirs, entericformulations or pastes. Compositions intended for oral use may beprepared according to any method known in the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore sweetening agents, bittering agents, flavoring agents, coloringagents and preserving agents in order to provide pharmaceuticallyelegant and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 (all incorporated herein by reference in theirentirety) to form osmotic therapeutic tablets for controlled release.

Oral formulations include hard gelatin capsules, wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin. Capsules may also be softgelatin capsules, wherein the active ingredient is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.

In one embodiment, the compounds of formula (I) may be administered inchewable tablet compositions or soft chewable compositions such as thosedescribed in US 2013/0203692 A1, US 2010/0087492, US 2006/0222684, US2004/0151759, U.S. Pat. No. 7,955,632, all incorporated herein byreference. The veterinary compositions may be in the form of a softchewable formulation (“soft chew”) which is palatable and acceptable tothe animal. In addition to the active ingredient(s), the soft chews ofthe invention may include one or more of the following components: asolvent or mixture of solvents, one or more fillers, one or morebinders, one or more surfactants, one or more humectants, one or morelubricants, one or more disintegrants, one or more colorants, one ormore antimicrobial agents, one or more antioxidants, one or more pHmodifiers and one or more flavoring agents.

Solvents that may be used in the compositions of the invention include,but are not limited to, various grades of liquid polyethylene glycol(PEG) including PEG 200, PEG 300, PEG 400 and PEG 540; propylenecarbonate; alcohols including ethanol, isopropanol and benzyl alcohol;propylene glycol; triglycerides including, but not limited tocaprylic/capric triglyceride, caprylic/capric/linoleic triglyceride(e.g. MIGLYOL® 810 and 812, caprylic/capric/succinic triglyceride,propylene glycol dicaprylate/dicaprate, and the like; water, sorbitolsolution, glycerol caprylate/caprate and polyglycolized glycerides(GELUCIRE®), or a combination thereof.

Various fillers known in the art may be used in the soft chewablecompositions of the invention. Fillers include, but are not limited to,corn starch, pre-gelatinized corn starch, soy protein fines, corn cob,and corn gluten meal, and the like. In some embodiments, a combinationof two or more fillers may be used in the compositions.

Binders that may be used in the compositions of the invention include,but are not limited to, polyvinylpyrrolidone (e.g. Povidone),cross-linked polyvinylpyrrolidone (Crospovidone), polyethylene glycolsof various grades including PEG 3350, PEG 4000, PEG 6000, PEG 8000 andeven PEG 20,000, and the like; co-polymers of vinylpyrrolidone and vinylacetate (e.g. Copovidone) such as the product sold by BASF by thetradename Kollidon® VA 64 and the like; starch such as potato starch,tapioca starch or corn starch; molasses, corn syrup, honey, maple syrupand sugars of various types; or a combination of two or more binders.

Humectants that may be used in the compositions include, but are notlimited to, glycerol (also referred to herein as glycerin), propyleneglycol, cetyl alcohol and glycerol monostearate, and the like.Polyethylene glycols of various grades may also be used as humectants.

Surfactants may be present in the composition to improve theirsolubility and absorption after ingestion. Surfactants are typicallypresent in a concentration of about 1 to 10% (w/w), more typically about1 to about 5% (w/w). Examples of surfactants that may be used in thecompositions include, but are not limited to, glyceryl monooleate,polyoxyethylene sorbitan fatty acid esters, sorbitan esters includingsorbitan monooleate (Span® 20), polyvinyl alcohol, polysorbatesincluding polysorbate 20 and polysorbate 80, d-α-tocopheryl polyethyleneglycol 1000 succinate (TPGS), sodium lauryl sulfate, co-polymers ofethylene oxide and propylene oxide (e.g. poloxamers such as LUTROL® F87and the like), polyethylene glycol castor oil derivatives includingpolyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castoroil (Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor®RH60); propylene glycol monolaurate (LAUROGLYCOL®); glyceride estersincluding glycerol caprylate/caprate (CAPMUL® MCM), polyglycolizedglycerides (GELUCIRE®), PEG 300 caprylic/capric glycerides (Softigen®767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleicglycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil®M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl40 stearate (PEG 1750 monostearate), and the like.

The inventive formulations may contain other inert ingredients such asantioxidants, preservatives, or pH stabilizers. These compounds are wellknown in the formulation art. Antioxidants may be added to thecompositions of the invention to inhibit degradation of the activeagents. Suitable antioxidants include, but are not limited to, alphatocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid,sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylatedhydroxy anisole), BHT (butylated hydroxy toluene) monothioglycerol andthe like.

The compositions of the invention may also include one or morelubricants and/or processing aids. In some cases, thelubricant/processing aid may also behave as a solvent, and accordingly,there some of the components of the inventive compositions may have dualfunctions. Lubricants/processing aids include, but are not limited topolyethylene glycols of various molecular weight ranges including PEG3350 (Dow Chemical) and PEG 4000, corn oil, mineral oil, hydrogenatedvegetable oils (STEROTEX or LUBRITAB), peanut oil and/or castor oil.

Many flavoring agents may be used in the compositions of the inventionto improve the palatability of the oral veterinary formulations.Preferred flavoring agents are those that are not derived from animalsources. In various embodiments, flavoring components derived fromfruit, meat (including, but not limited to pork, beef, chicken, fish,poultry, and the like), vegetable, cheese, bacon, cheese-bacon and/orartificial flavorings may be used. A flavoring component is typicallychosen based upon consideration related to the organism that will beingesting the soft chew. For example, a horse may prefer an appleflavoring component, while a dog may prefer a meat flavoring component.Although flavoring components derived from non-animal sources arepreferred, in some embodiments, natural flavors containing beef or liverextracts, etc., may be used such as braised beef flavor artificialpowdered beef flavor, roast beef flavor and corned beef flavor amongothers.

In another embodiment of the invention, the active composition may beadministered via a drench, and may be administered either topically ororally. Drench formulations are those in which the liquid-containingcompositions of the invention are administered to the mouth or throat ofthe animal, or poured onto the skin or coat of the animal.

The compositions of the invention may also be in the form ofoil-in-water or water-in-oil emulsions. The oily phase maybe a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin or mixtures of these. Suitable emulsifyingagents include naturally-occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monooleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, bittering agents, flavoring agents, and/orpreservatives.

In one embodiment, the composition of the invention may be in the formof a microemulsion. Microemulsions are well suited as the liquid carriervehicle. Microemulsions are quaternary systems comprising an aqueousphase, an oily phase, a surfactant and a co-surfactant. They aretranslucent and isotropic liquids.

Microemulsions are composed of stable dispersions of microdroplets ofthe aqueous phase in the oily phase or conversely of microdroplets ofthe oily phase in the aqueous phase. The size of these microdroplets maybe less than 200 nm (1000 to 100,000 nm for emulsions). The interfacialfilm may be composed of an alternation of surface-active (SA) andco-surface-active (Co-SA) molecules which, by lowering the interfacialtension, allows the microemulsion to be formed spontaneously.

In one embodiment of the oily phase, the oily phase may be formed frommineral or vegetable oils, from unsaturated polyglycosylated glyceridesor from triglycerides, or alternatively from mixtures of such compounds.In one embodiment of the oily phase, the oily phase may be comprised oftriglycerides; in another embodiment of the oily phase, thetriglycerides are medium-chain triglycerides, for example C₈-C₁₀caprylic/capric triglyceride. In another embodiment of the oily phasemay represent a % v/v range of about 2 to about 15%; about 7 to about10%; and about 8 to about 9% v/v of the microemulsion.

The aqueous phase may include, for example water or glycol derivatives,such as propylene glycol, glycol ethers, polyethylene glycols orglycerol. In one embodiment, the glycol may be propylene glycol,diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether ormixtures thereof. Generally, the aqueous phase will represent aproportion from about 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion may include diethylene glycolmonoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzedC₈-C₁₀ glycerides or polyglyceryl-6 dioleate. In addition to thesesurfactants, the co-surfactants may include short-chain alcohols, suchas ethanol and propanol.

Some compounds are common to the three components discussed above, i.e.,aqueous phase, surfactant and co-surfactant. However, it is well withinthe skill level of the practitioner to use different compounds for eachcomponent of the same formulation. In one embodiment for the amount ofsurfactant/co-surfactant, the co-surfactant to surfactant ratio will befrom about 1/7 to about 1/2. In another embodiment for the amount ofco-surfactant, there will be from about 25 to about 75% v/v ofsurfactant and from about 10 to about 55% v/v of co-surfactant in themicroemulsion.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions may contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents include naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water may provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and/or coloring agent(s).

In another embodiment of the invention, the composition may be in pasteform. Examples of embodiments in a paste form include, but are notlimited to, those described in U.S. Pat. Nos. 6,787,342 and 7,001,889(each of which are incorporated herein by reference). In addition to thecompounds of the invention, the paste may further contain fumed silica;a viscosity modifier; a carrier; optionally, an absorbent; andoptionally, a colorant, stabilizer, surfactant, or preservative.

In one embodiment of the formulation, the formulation may be a pastecontaining the compounds of the invention, fumed silica, a viscositymodifier, an absorbent, a colorant; and a hydrophilic carrier which istriacetin, a monoglyceride, a diglyceride, or a triglyceride.

The paste may also include a viscosity modifier. Suitable viscositymodifiers include, but are not limited to, polyethylene glycols (PEG)including, but not limited to, PEG 200, PEG 300, PEG 400, PEG 600;monoethanolamine, triethanolamine, glycerol, propylene glycol,polyoxyethylene (20) sorbitan mono-oleate (polysorbate 80 or Tween 80),or poloxamers (e.g., Pluronic L 81); an absorbent such as magnesiumcarbonate, calcium carbonate, starch, and cellulose and its derivatives;and a colorant including, but not limited to, titanium dioxide ironoxide, or FD&C Blue #1 Aluminum Lake.

In some embodiments, the compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example, as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Co-solventssuch as ethanol, propylene glycol, glycerol formal or polyethyleneglycols may also be used. Preservatives, such as phenol or benzylalcohol, may be used.

In addition, sterile, fixed oils may be conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Topical, dermal and subdermal formulations may include, by way ofnon-limiting example, emulsions, creams, ointments, gels, pastes,powders, shampoos, pour-on formulations, ready-to-use formulations,spot-on solutions and suspensions, dips and sprays. Topical applicationof an inventive compound or of a composition including at least oneinventive compound among active agent(s) therein, in the form of aspot-on, spray-on or pour-on composition, may allow for the inventivecomposition to be absorbed through the skin to achieve systemic levels,distributed through the sebaceous glands or on the surface of the skinachieving levels throughout the coat. When the compound is distributedthrough the sebaceous glands, they may act as a reservoir, whereby theremay be a long-lasting effect (up to several months) effect. Spot-onformulations are typically applied in a localized region which refers toan area other than the entire animal. In one embodiment, the locationmay be between the shoulders. In another embodiment it may be a stripe,e.g. a stripe from head to tail of the animal.

Pour-on formulations are described in U.S. Pat. No. 6,010,710, alsoincorporated herein by reference. Pour-on formulations may beadvantageously oily, and generally comprise a diluent or vehicle andalso a solvent (e.g. an organic solvent) for the active ingredient ifthe latter is not soluble in the diluent.

Organic solvents that can be used in the invention include, but are notlimited to, acetyltributyl citrate, fatty acid esters such as thedimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzylalcohol, ethyl alcohol, butyl diglycol, dimethylacetamide,dimethylformamide, dimethyl sulfoxide, dipropylene glycol n-butyl ether,ethanol, isopropanol, methanol, ethylene glycol monoethyl ether,ethylene glycol monomethyl ether, monomethylacetamide, dipropyleneglycol monomethyl ether, liquid polyoxyethylene glycols, propyleneglycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), propylene carbonate,diethylene glycol monoethyl ether, ethylene glycol, triacetin, C₁-C₁₀esters of carboxylic acids such as butyl or octyl acetate, and diethylphthalate, or a mixture of at least two of these solvents.

The solvent will be used in proportion with the concentration of theactive agent compound and its solubility in this solvent. It will besought to have the lowest possible volume. The vehicle makes up thedifference to 100%.

A vehicle or diluent for the formulations may include dimethyl sulfoxide(DMSO), glycol derivatives such as, for example, propylene glycol,glycol ethers, polyethylene glycols or glycerol. As vehicle or diluent,mention may also be made of plant oils such as, but not limited tosoybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil,grape seed oil, sunflower oil, etc.; mineral oils such as, but notlimited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclichydrocarbons or alternatively, for example, medium-chain (such as C₈ toC₁₂) triglycerides.

In another embodiment of the invention, an emollient and/or spreadingand/or film-forming agent may be added. In one embodiment, the emollientand/or spreading and/or film-forming agent may be:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;lecithin, sodium carboxymethylcellulose, silicone oils,polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils),for example those containing silanol functionalities, or a 45V2 oil,

(b) anionic surfactants such as alkaline stearates, sodium, potassium orammonium stearates; calcium stearate, triethanolamine stearate; sodiumabietate; alkyl sulphates (e.g. sodium lauryl sulphate and sodium cetylsulphate); sodium dodecylbenzenesulphonate, sodiumdioctylsulphosuccinate; fatty acids (e.g. those derived from coconutoil),

(c) cationic surfactants include water-soluble quaternary ammonium saltsof formula N⁺R′R″R′″R″″, Y⁻ in which the radicals R are optionallyhydroxylated hydrocarbon radicals and Y⁻ is an anion of a strong acidsuch as the halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is among the cationic surfactants whichcan be used,

(d) amine salts of formula N⁺ HR′R″R′″ in which the radicals R areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants which can be used,

(e) nonionic surfactants such as sorbitan esters, which are optionallypolyoxyethylenated (e.g. polysorbate 80), polyoxyethylenated alkylethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrolether; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide,

(f) amphoteric surfactants such as the substituted lauryl compounds ofbetaine; or

(g) a mixture of at least two of these agents.

In one embodiment of the amount of emollient, the emollient used may bein a proportion of from about 0.1 to 50% or 0.25 to 5%, by volume. Inanother embodiment, the emollient used may be in a proportion of fromabout 0.1% to about 30%, about 1% to about 30%, about 1% to about 20%,or about 5% to about 20% by volume.

In another embodiment of the invention, the composition may be inready-to-use solution form as is described in U.S. Pat. No. 6,395,765,incorporated herein by reference. In addition to the compounds of theinvention, the ready-to-use solution may contain a crystallizationinhibitor and an organic solvent or a mixture of organic solvents. Insome embodiments, water may be included with the organic solvent.

In various embodiments of the invention, the compositions may include acrystallization inhibitor in an amount of about 1 to about 50% (w/v) orabout 5 to about 40% (w/v) based on the total weight of the formulation.In other embodiments, the amount of crystallization inhibitor in theinventive formulations may be about 1% to about 30%, about 5% to about20%, about 1% to about 15%, or about 1% to about 10% (w/w). The type ofcrystallization inhibitor used in the inventive formulations is notlimited as long as it functions to inhibit crystallization of the activeor inactive agents from the formulation. For example, in certainembodiments of the invention, a solvent or co-solvent of the formulationmay also function as a crystallization inhibitor if it sufficientlyinhibits the formation of crystals from forming over time when theformulation is administered.

Crystallization inhibitors which are useful for the invention include,but are not limited to:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,dimethylformamide, dimethylacetamide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, mannitol, glycerol, sorbitol or polyoxyethylenatedesters of sorbitan; lecithin or sodium carboxymethylcellulose; oracrylic derivatives, such as acrylates or methacrylates or polymers orcopolymers thereof, polyethyleneglycols (PEG) or polymers containingpolyethyleneglycols, such as glycofurol and the like, and others;

(b) anionic surfactants, such as alkaline stearates (e.g. sodium,potassium or ammonium stearate); calcium stearate or triethanolaminestearate; sodium abietate; alkyl sulphates, which include but are notlimited to sodium lauryl sulphate and sodium cetyl sulphate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids (e.g. coconut oil);

(c) cationic surfactants, such as water-soluble quaternary ammoniumsalts of formula N⁺R′R″R′″R″″Y⁻, in which the R radicals are identicalor different optionally hydroxylated hydrocarbon radicals and Y⁻ is ananion of a strong acid, such as halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used;

(d) amine salts of formula N⁺HR′R″R′″, in which the R radicals areidentical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used;

(e) non-ionic surfactants, such as optionally polyoxyethylenated estersof sorbitan, e.g. Polysorbate 80, or polyoxyethylenated alkyl ethers;polyethylene glycol stearate, polyoxyethylenated derivatives of castoroil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids or copolymers of ethylene oxide and ofpropylene oxide;

(f) amphoteric surfactants, such as substituted lauryl compounds ofbetaine;

(g) a mixture of at least two of the compounds listed in (a)-(f) above;or

(h) an organic solvent or mixture of solvents which inhibit theformation of crystals or amorphous solid after the formulation isadministered.

In one embodiment of the crystallization inhibitor, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents will be selected from the compoundsmentioned above as crystallization inhibitor.

In some embodiments, the organic solvent(s) may have a dielectricconstant of between about 10 and about 35 or between about 20 and about30. In other embodiments, the organic solvent may have a dielectricconstant of between about 10 and about 40 or between about 20 and about30. The content of this organic solvent or mixture of solvents in theoverall composition is not limited and will be present in an amountsufficient to dissolve the desired components to a desiredconcentration. As discussed above, the organic solvent may also functionas a crystallization inhibitor in the formulation.

In some embodiments, one or more of the organic solvent(s) may have aboiling point of below about 100° C., or below about 80° C. In otherembodiments, the organic solvent(s) may have a boiling point of belowabout 300° C., below about 250° C., below about 230° C., below about210° C. or below about 200° C.

In some embodiments where there is a mixture of solvents, i.e. a solventand a co-solvent, the solvents may be present in the composition in aweight/weight (W/W) ratio of about 1/50 to about 1/1. Typically thesolvents will be in a ratio of about 1/30 to about 1/1, about 1/20 toabout 1/1, or about 1/15 to about 1/1 by weight. Preferably, the twosolvents will be present in a weight/weight ratio of about 1/15 to about1/2. In some embodiments, at least one of the solvents present may actas to improve solubility of the active agent or as a drying promoter. Inparticular embodiments, at least one of the solvents will be misciblewith water.

The formulation may also comprise an antioxidizing agent intended toinhibit oxidation in air, this agent may be present in a proportion ofabout 0.005 to about 1% (w/v), about 0.01 to about 0.1%, or about 0.01to about 0.05%.

In one embodiment of the film-forming agent, the agents are of thepolymeric type which include but are not limited to the various gradesof polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents include butare not limited to those made of non-ionic surfactants; in anotherembodiment of the surface active agents, the agent is apolyoxyethylenated esters of sorbitan and in yet another embodiment ofthe surface-active agent, the agents include the various grades ofpolysorbate, for example Polysorbate 80.

In another embodiment of the invention, the film-forming agent and thesurface-active agent may be incorporated in similar or identical amountswithin the limit of the total amounts of crystallization inhibitormentioned elsewhere.

The crystallization inhibitor inhibits the formation of crystals on thecoat, and improves the maintenance of the cosmetic appearance of theskin or fur; that is to say without a tendency towards sticking ortowards a sticky appearance, despite the high concentration of activematerial. Substances other than those mentioned herein may be used ascrystallization inhibitors in the present invention. In one embodiment,the effectiveness of the crystallization inhibitor may be demonstratedby a test according to which 0.3 mL of a solution comprising 10% (w/v)of the active agent in an appropriate solvent as defined above, and 10%(w/v) of the compound acting as a crystallization inhibitor are placedon a glass slide at 20° C. for 24 hours, after which fewer than 10crystals, preferably 0 crystals, are seen with the naked eye on theglass slide.

In one embodiment of the antioxidizing agents, the agents are thoseconventional in the art and include but are not limited to butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulphate or a mixture of atleast two compounds with antioxidant properties.

The formulation adjuvants discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques. These concentrated compositions are generally preparedby simple mixing of the constituents as defined above; advantageously,the starting point is to mix the active material in the main solvent andthen the other ingredients or adjuvants are added.

The volume of the formulation applied will depend on the type of animaland the size of the animal as well as the strength of the formulationand the potency of the active agents. In one embodiment, an amount ofabout 0.1 to about 20 ml of the formulation may be applied to theanimal. In other embodiment for the volume, the volume may be about 0.1to about 10 ml, about 0.1 to about 5 ml, about 0.5 ml to about 10 ml, orabout 0.3 to about 3 ml.

In another embodiment of the invention, application of a spot-onformulation according to the present invention may also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on formulations provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

For spot-on formulations, the carrier may be a liquid carrier vehicle asdescribed in U.S. Pat. No. 6,426,333 (incorporated herein by reference),which in one embodiment of the spot-on formulation may comprise asolvent or mixture of solvents including, but not limited to, acetone,an aliphatic alcohol such as methanol, ethanol, propanol, butanol,isopropanol, pentanol, hexanol, heptanol, octanol, nonanol,cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol and thelike; an aromatic alcohol such as phenol, cresol, naphthol, benzylalcohol and the like; acetonitrile, butyl diglycol, an organic amidesuch as dimethylacetamide, dimethylformamide, monomethylacetamide,2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone and the like;propylene or ethylene carbonate, dimethylsulfoxide (DMSO), a glycolpolymer or an ether thereof, such as polyethylene glycol (PEG) ofvarious grades, polypropylene glycols of various grades, dipropyleneglycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycolmonomethyl ether, dipropylene glycol monomethyl ether, diethylene glycolmonoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters,such as the diethyl ester or diisobutyl adipate, or a mixture of atleast two of these solvents.

The liquid carrier vehicle may optionally contain a crystallizationinhibitor including, but not limited to, those described in (a) to (h)above, or a compound that may act both as a solvent and acrystallization inhibitor (as defined above), or a mixture of thesecrystallization inhibitors.

Spot-on formulations may be prepared by dissolving the activeingredients into the pharmaceutically or veterinary acceptable vehicle.Alternatively, the spot-on formulation may be prepared by encapsulationof the active ingredient to leave a residue of the therapeutic agent onthe surface of the animal. These formulations will vary with regard tothe weight of the therapeutic agent in the combination depending on thespecies of host animal to be treated, the severity and type of infectionand the body weight of the host.

Dosage forms may typically contain from about 0.1 mg to about 5 g. Inother embodiments, the dosage form may contain about 0.5 mg to about 5 gof an active agent. In one embodiment of the dosage form, the dosage maycontain from about 1 mg to about 500 mg of an active agent, typicallyabout 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg,about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000mg.

In one embodiment of the invention, the active agent may be present inthe formulation at a concentration of about 0.05 to about 10%weight/volume. In another embodiment of the invention, the active agentmay be present in the formulation as a concentration from about 0.1 toabout 2% weight/volume. In yet another embodiment of the invention, theactive agent may be present in the formulation as a concentration fromabout 0.25 to about 1.5% weight/volume. In still another embodiment ofthe invention, the active agent may be present in the formulation as aconcentration about 1% weight/volume.

II. Methods of Treatment:

As discussed above, the compounds of formula (I) are effective againstendoparasites and may be used to treat and prevent parasitic infectionsin or on animals. For avoidance of doubt, an animal includes mammals(including humans), birds or fish. In one embodiment, the presentinvention provides a method of treating or preventing an endoparasiteinfection in or on an animal comprising administering anendoparasiticidally effective amount of a compound of formula (I), orveterinarily or pharmaceutically acceptable salts thereof, or acomposition of the invention, to the animal.

The compounds of formula (I) are also effective against ectoparasitesand may be used to treat and prevent ectoparasitic infestations onanimals. In another embodiment, the present invention provides a methodof treating or preventing an ectoparasitic infestation on an animalcomprising administering an ectoparasiticidally effective amount of acompound of formula (I), or pharmaceutically acceptable salts thereof,or a composition of the invention, to the animal.

In another embodiment, the invention provides a method for treating orpreventing an endoparasitic infection and an ectoparasitic infestationin and on an animal, comprising administering a composition comprisingan effective amount of a compound of formula (I) in combination with aneffective amount of at least a second active agent, or pharmaceuticallyacceptable salts thereof, to the animal.

In still another embodiment of the invention, a method is provided forthe treatment or prevention of a parasitic infestation at a locus, whichcomprises administering or applying a parasiticidally effective amountof a compound of formula (I), or pharmaceutically acceptable saltsthereof, to the locus. With respect to animal health applications,“locus” is intended to mean a habitat, breeding ground, area, materialor environment in which a parasite is growing or may grow, excluding inor on an animal.

In another embodiment, the invention provides methods and uses of thecompounds of formula (I) for controlling pests in plants and crops orfor protecting wood-containing structures.

Mammals which can be treated include but are not limited to humans,cats, dogs, cattle, chickens, bison, deer, goats, horses, llamas,camels, pigs, sheep and yaks. In one embodiment of the invention, themammals treated are humans, cats or dogs.

In one embodiment of the invention, the compounds of formula (I) havebeen superior efficacy against endoparasites, and in particular againstendoparasites that are resistant to active agents of the macrocycliclactone class. In one embodiment, the compounds and compositions of theinvention are effective for controlling Haemonchus contortus, Ostertagiacircumcincta and Trichostrongylus colubriformis in mammals or birds.

In another embodiment, the invention provides a method for treating anparasitic infestation or infection in an animal, comprisingadministering an effective amount of an anthelmintic compound of theinvention in combination with an effective amount of activators ofinvertebrate GABA receptors including an avermectin or milbemycin to theanimal in need thereof. Avermectins that may be used in combination withthe compounds of the invention include, but are not limited toabamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin,latidectin, lepimectin and selamectin. Milbemycins compounds that may beused in combination with the compounds of the invention include, but arenot limited to, milbemectin, milbemycin D, moxidectin and nemadectin.Also included are the 5-oxo and 5-oxime derivatives of said avermectinsand milbemycins.

In one embodiment, the compounds and compositions of the invention maybe used for treating or preventing an endoparasitic infection of thefollowing parasite: Anaplocephala (Anoplocephala), Ancylostoma, Necator,Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia,Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus,Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria,Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema,Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus,Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris,Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides,Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorus,Uncinaria, Wuchereria, and combinations thereof.

In a particularly preferred embodiment of the invention, the compoundsand compositions of the invention are used to treat or prevent aninfection by Dirofilaria immitis. The compounds of formula (I) have beenfound to be highly effective against D. immitis microfilaria and L4larvae in vitro and have also been found to be effective for protectinganimals from infection by Dirofilaria immitis in vivo. Thus, thecompounds of formula (I) may be used to protect animals from developingheartworm disease by killing the immature stages of D. immitis beforethey can develop into adult worms. In one embodiment, the compounds offormula (I) and compositions comprising the compounds may be used toprevent the development of heartworm disease by killing immature stagesof D. immitis that are resistant to macrocyclic lactones. In anotherembodiment the compounds and compositions of the invention are used totreat or prevent an infection by Dirofilaria repens or Dirofilariahongkongensis.

In another embodiment of the invention, the parasite is Haemonchuscontortus, Ostertagia circumcincta, Trichostrongylus axei,Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battusand combinations thereof.

In another embodiment for treatment against endoparasites, andectoparasites when combined with ectoparasiticidal agents, theectoparasite is one or more insect or arachnid including those of thegenera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus,Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes,Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes,Trichodectes, and Felicola.

In another embodiment for the treatment against ectoparasites, theectoparasite is from the genera Ctenocephalides, Rhipicephalus,Dermacentor, Ixodes and/or Boophilus. The ectoparasites treated includebut are not limited to fleas, ticks, mites, mosquitoes, flies, lice,blowfly and combinations thereof. Specific examples include but are notlimited to cat and dog fleas (Ctenocephalides felis, Ctenocephalidesspp. and the like), ticks (Rhipicephalus spp., Ixodes spp., Dermacentorspp., Amblyomma spp. and the like), and mites (Demodex spp., Sarcoptesspp., Otodectes spp. and the like), lice (Trichodectes spp.,Cheyletiella spp., Linognathus spp., and the like), mosquitoes (Aedesspp., Culex spp., Anopheles spp., and the like) and flies (Haematobiaspp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., andthe like). In yet another embodiment for the treatment againstectoparasites, the ectoparasite is a flea and/or tick.

Additional examples of ectoparasites include but are not limited to thetick genus Boophilus, especially those of the species microplus (cattletick), decoloratus and annulates; myiasis such as Dermatobia hominis(known as Berne in Brazil) and Cochliomyia hominivorax (greenbottle);sheep myiasis such as Lucilia sericata, Lucilia cuprina (known asblowfly strike in Australia, New Zealand and South Africa). Fliesproper, namely those whose adult constitutes the parasite, such asHaematobia irritans (horn fly); lice such as Linognathus vitulorum,etc.; and mites such as Sarcoptes scabiei and Psoroptes ovis. The abovelist is not exhaustive and other ectoparasites are well known in the artto be harmful to animals and humans. These include, for examplemigrating dipterous larvae.

In another embodiment of the invention, the compounds and compositionsof the invention are suitable for controlling pests such as insectsselected from the group consisting of Blatella germanica, Heliothisvirescens, Leptinotarsa decemlineata, Tetramorium caespitum andcombinations thereof.

The phytoparasitic nematodes include, for example, Anguina spp.,Aphelenchoides spp., Belonolaimus spp., Bursaphelenchus spp.,Ditylenchus dipsaci, Globodera spp., Helicotylenchus spp., Heteroderaspp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholussimilis, Rotylenchus spp., Trichodorus spp., Tylenchorhynchus spp.,Tylenchulus spp., Tylenchulus semipenetrans, and Xiphinema spp.

In addition, with or without the other pesticidal agents added to thecomposition, the invention can also be used to treat other pests whichinclude but are not limited to pests:

(1) from the order of Isopoda, for example Oniscus asellus,Armadillidium vulgare and Porcellio scaber;

(2) from the order of Diplopoda, for example Blaniulus guttulatus;

(3) from the order of Chilopoda, for example Geophilus sarcophagus andScutigera Spp.;

(4) from the order of Symphyla, for example Scutigerella immaculata;

(5) from the order of Thysanura, for example Lepisma saccharina;

(6) from the order of Collembola, for example Onychiurus armatus;

(7) from the order of Blattaria, for example Blatta orientalis,Periplaneta americana, Leucophaea maderae and Blattella germanica;

(8) from the order of Hymenoptera, for example Diprion spp., Hoplocampaspp., Lasius spp., Monomorium pharaonis and Vespa spp.;

(9) from the order of Siphonaptera, for example Xenopsylla cheopis andCeratophyllus spp.;

(10) from the order of Anoplura (Phthiraptera), for example, Damaliniaspp., Haematopinus spp., Linognathus spp., Pediculus spp., Trichodectesspp.;

(11) from the class of Arachnida, for example, Acarus siro, Aceriasheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp.,Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp.,Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pyri,Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Hyalomma spp.,Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychusspp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora,Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp.,Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus, Stenotarsonemus spp.,Tarsonemus spp., Tetranychus spp., Vasates lycopersici;

(12) from the class of Bivalva, for example, Dreissena spp.;

(13) from the order of Coleoptera, for example, Acanthoscelidesobtectus, Adoretus spp., Agelastica alni, Agriotes spp., Amphimallonsolstitialis, Anobium punctatum, Anoplophora spp., Anthonomus spp.,Anthrenus spp., Apogonia spp., Atomaria spp., Attagenus spp., Bruchidiusobtectus, Bruchus spp., Ceuthorhynchus spp., Cleonus mendicus, Conoderusspp., Cosmopolites spp., Costelytra zealandica, Curculio spp.,Cryptorhynchus lapathi, Dermestes spp., Diabrotica spp., Epilachna spp.,Faustinus cubae, Gibbium psylloides, Heteronychus arator, Hylamorphaelegans, Hylotrupes bajulus, Hypera postica, Hypothenemus spp.,Lachnosterna consanguinea, Leptinotarsa decemlineata, Lissorhoptrusoryzophilus, Lixus spp., Lyctus spp., Meligethes aeneus, Melolonthamelolontha, Migdolus spp., Monochamus spp., Naupactus xanthographus,Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis,Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae,Phyllophaga spp., Popillia japonica, Premnotrypes spp., Psylliodeschrysocephala, Ptinus spp., Rhizobius ventralis, Rhizopertha dominica,Sitophilus spp., Sphenophorus spp., Sternechus spp., Symphyletes spp.,Tenebrio molitor, Tribolium spp., Trogoderma spp., Tychius spp.,Xylotrechus spp., Zabrus spp.;

(14) from the order of Diptera, for example, Aedes spp., Anopheles spp.,Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata,Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp.,Cuterebra spp., Dacus oleae, Dermatobia hominis, Drosophila spp., Fanniaspp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp.,Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp.,Oscinella fit, Pegomyia hyoscyami, Phorbia spp., Stomoxys spp., Tabanusspp., Tannia spp., Tipula paludosa, Wohlfahrtia spp.;

(15) from the class of Gastropoda, for example, Arion spp., Biomphalariaspp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp.,Oncomelania spp., Succinea spp.;

(16) from the class of helminths, for example, Ancylostoma duodenale,Ancylostoma ceylanicum, Ancylostoma braziliensis, Ancylostoma spp.,Ascaris lumbricoides, Ascaris spp., Brugia malayi, Brugia timori,Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp.,Dicrocoelium spp, Dictyocaulus filaria, Diphyllobothrium latum,Dracunculus medinensis, Echinococcus granulosus, Echinococcusmultilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp.,Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa Loa,Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocercavolvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp.,Strongyloides fuelleborni, Strongyloides stercoralis, Strongyloidesspp., Taenia saginata, Taenia solium, Trichinella spiralis, Trichinellanativa, Trichinella britovi, Trichinella nelsoni, Trichinellapseudopsiralis, Trichostrongulus spp., Trichuris trichiura, Wuchereriabancrofti;

(17) from the order of Heteroptera, for example, Anasa tristis,Antestiopsis spp., Blissus spp., Calocoris spp., Campylomma livida,Cavelerius spp., Cimex spp., Creontiades dilutus, Dasynus piperis,Dichelops furcatus, Diconocoris hewetti, Dysdercus spp., Euschistusspp., Eurygaster spp., Heliopeltis spp., Horcias nobilellus, Leptocorisaspp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae,Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp.,Psallus seriatus, Pseudacysta persea, Rhodnius spp., Sahlbergellasingularis, Scotinophora spp., Stephanitis nashi, Tibraca spp., Triatomaspp.;

(18) from the order of Homoptera, for example, Acyrthosipon spp.,Aeneolamia spp., Agonoscena spp., Aleurodes spp., Aleurolobusbarodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui,Aonidiella spp., Aphanostigma piri, Aphis spp., Arboridia apicalis,Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani,Bemisia spp., Brachycaudus helichrysii, Brachycolus spp., Brevicorynebrassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacunalanigera, Cercopidae, Ceroplastes spp., Chaetosiphon fragaefolii,Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola,Chrysomphalus ficus, Cicadulina mbila, Coccomytilus haul, Coccus spp.,Cryptomyzus ribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp.,Diaspis spp., Doralis spp., Drosicha spp., Dysaphis spp., Dysmicoccusspp., Empoasca spp., Eriosoma spp., Erythroneura spp., Euscelisbilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterusarundinis, Icerya spp., Idiocerus spp., Idioscopus spp., Laodelphaxstriatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi,Macrosiphum spp., Mahanarva fimbriolata, Melanaphis sacchari,Metcalfiella spp., Metopolophium dirhodum, Monellia costalis,Monelliopsis pecanis, Myzus spp., Nasonovia ribisnigri, Nephotettixspp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga,Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pemphigus spp.,Peregrinus maidis, Phenacoccus spp., Phloeomyzus passerinii, Phorodonhumuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp.,Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcusspp., Psylla spp., Pteromalus spp., Pyrilla spp., Quadraspidiotus spp.,Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp.,Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus,Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina,Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis spp.,Toxoptera spp., Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp.,Unaspis spp., Viteus vitifolii;

(19) from the order of Isoptera, for example, Reticulitermes spp.,Odontotermes spp.;

(20) from the order of Lepidoptera, for example, Acronicta major, Aedialeucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathrabrassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana,Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo spp.,Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus spp., Eariasinsulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp.,Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp.,Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padella,Laphygma spp., Lithocolletis blancardella, Lithophane antennata,Loxagrotis albicosta, Lymantria spp., Malacosoma neustria, Mamestrabrassicae, Mods repanda, Mythimna separata, Oria spp., Oulema oryzae,Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella,Pieris spp., Plutella xylostella, Prodenia spp., Pseudaletia spp.,Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesiagemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana,Trichoplusia spp.;

(21) from the order of Orthoptera, for example, Acheta domesticus,Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaeamaderae, Locusta spp., Melanoplus spp., Periplaneta americana,Schistocerca gregaria;

(22) from the order of Thysanoptera, for example, Baliothrips biformis,Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothripsfemoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothripsspp., Taeniothrips cardamoni, Thrips spp.;

(23) from the class of Protozoa, for example, Eimeria spp.

In each aspect of the invention, the compounds and compositions of theinvention can be applied against a single pest or combinations thereof.

III. Mixtures with Other Active Agents

In another embodiment, the compositions comprising the cyclicdepsipeptides of formula (I) may also include other veterinarytherapeutic agents. Veterinary pharmaceutical agents that may beincluded in the compositions of the invention are well-known in the art(see e.g. Plumb' Veterinary Drug Handbook, 5^(th) Edition, ed. Donald C.Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual,9^(th) Edition, (January 2005)) and include but are not limited toacarbose, acepromazine maleate, acetaminophen, acetazolamide,acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine,acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil,allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate,aminocaproic acid, aminopentamide hydrogen sulfate,aminophylline/theophylline, amiodarone, amitriptyline, amlodipinebesylate, ammonium chloride, ammonium molybdate, amoxicillin,clavulanate potassium, amphotericin B deoxycholate, amphotericin Blipid-based, ampicillin, amprolium, antacids (oral), antivenin,apomorphione, apramycin sulfate, ascorbic acid, asparaginase, aspiring,atenolol, atipamezole, atracurium besylate, atropine sulfate, auranofin,aurothioglucose, azaperone, azathioprine, azithromycin, baclofen,barbiturates, benazepril, betamethasone, bethanechol chloride,bisacodyl, bismuth sub salicylate, bleomycin sulfate, boldenoneundecylenate, bromides, bromocriptine mesylate, budesonide,buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline,calcitonin salmon, calcitrol, calcium salts, captopril, carbenicillinindanyl sodium, carbimazole, carboplatin, carnitine, carprofen,carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon,cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitinsodium, cefpodoxime proxetil, ceftazidime, ceftiofur sodium, ceftiofur,ceftriaxone sodium, cephalexin, cephalosporins, cephapirin, charcoal(activated), chlorambucil, chloramphenicol, chlordiazepoxide,chlordiazepoxide+/−clidinium bromide, chlorothiazide, chlorpheniraminemaleate, chlorpromazine, chlorpropamide, chlortetracycline, chorionicgonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride,cisplatin, citrate salts, clarithromycin, clemastine fumarate,clenbuterol, clindamycin, clofazimine, clomipramine, claonazepam,clonidine, cloprostenol sodium, clorazepate dipotassium, clorsulon,cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH),cosyntropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine,dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol,dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate,deracoxib, deslorelin acetate, desmopressin acetate,desoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol,dexraazoxane, dextran, diazepam, diazoxide (oral), dichlorphenamide,diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT),diltiazem, dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide,dinoprost tromethamine, diphenylhydramine, disopyramide phosphate,dobutamine, docusate/DSS, dolasetron mesylate, domperidone, dopamine,doramectin, doxapram, doxepin, doxorubicin, doxycycline, edetate calciumdisodium.calcium EDTA, edrophonium chloride, enalapril/enalaprilat,enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine,epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin,esmolol, estradiol cypionate, ethacrynic acid/ethacrynate sodium,ethanol (alcohol), etidronate sodium, etodolac, etomidate, euthanasiaagents w/pentobarbital, famotidine, fatty acids (essential/omega),felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil,florfenicol, fluconazole, flucytosine, fludrocortisone acetate,flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU),fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole(4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicinsulfate, glimepiride, glipizide, glucagon, glucocorticoid agents,glucosamine/chondroitin sulfate, glutamine, glyburide, glycerine (oral),glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane,hemoglobin glutamer-200 (OXYGLOBIN®®), heparin, hetastarch, hyaluronatesodium, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate,hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide,imidacloprid, imidocarb dipropinate, impenem-cilastatin sodium,imipramine, inamrinone lactate, insulin, interferon alfa-2a (humanrecombinant), iodide (sodium/potassium), ipecac (syrup), ipodate sodium,iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine,itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole,ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole,levetiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyroninesodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium,mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid,medetomidine, medium chain triglycerides, medroxyprogesterone acetate,megestrol acetate, melarsomine, melatonin, meloxican, melphalan,meperidine, mercaptopurine, meropenem, metformin, methadone,methazolamide, methenamine mandelate/hippurate, methimazole, methionine,methocarbamol, methohexital sodium, methotrexate, methoxyflurane,methylene blue, methylphenidate, methylprednisolone, metoclopramide,metoprolol, metronidaxole, mexiletine, mibolerlone, midazolam milbemycinoxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone,morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen,narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine,niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin,nitroprusside sodium, nizatidine, novobiocin sodium, nystatin,octreotide acetate, olsalazine sodium, omeprozole, ondansetron, opiateantidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxibutyninchloride, oxymorphone, oxytretracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide, paromomycin sulfate,parozetine, pencillamine, general information penicillins, penicillin G,penicillin V potassium, pentazocine, pentobarbital sodium, pentosanpolysulfate sodium, pentoxifylline, pergolide mesylate, phenobarbital,phenoxybenzamine, pheylbutazone, phenylephrine, phenypropanolamine,phenytoin sodium, pheromones, parenteral phosphate, phytonadione/vitaminK-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfatedglycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride,prazosin, prednisolone/prednisone, primidone, procainamide,procarbazine, prochlorperazine, propantheline bromide, propionibacteriumacnes injection, propofol, propranolol, protamine sulfate,pseudoephedrine, psyllium hydrophilic mucilloid, pyridostigmine bromide,pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine,rifampin, s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative,selamectin, selegiline/l-deprenyl, sertraline, sevelamer, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate,somatotropin, sotalol, spectinomycin, spironolactone, stanozolol,streptokinase, streptozocin, succimer, succinylcholine chloride,sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline, terbutaline sulfate, testosterone,tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopentalsodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium,tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate,tocainide, tolazoline, telfenamic acid, topiramate, tramadol,trimcinolone acetonide, trientine, trilostane, trimepraxine tartratew/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid,vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil,vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarinsodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zincacetate/zinc sulfate, zonisamide and mixtures thereof.

In one embodiment of the invention, arylpyrazole compounds such asphenylpyrazoles may be included in the veterinary compositions of theinvention. Arylpyrazoles are known in the art and are suitable forcombination with the cyclic depsipeptides of formula (I) in thecompositions of the invention. Examples of such arylpyrazole compoundsinclude but are not limited to those described in U.S. Pat. Nos.6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954,6,998,131 and 7,759,381 (all of which are incorporated herein byreference). A particularly preferred arylpyrazole active agent isfipronil.

In another embodiment of the invention, one or more macrocycliclactones, which act as an acaricide, an anthelmintic agent and/or aninsecticide, can be included in the compositions of the invention incombination with the compounds of formula (I). For the avoidance ofdoubt, the term “macrocyclic lactone” as used herein includes bothnaturally occurring and synthetic or semi-synthetic avermectin andmilbemycin compounds.

The macrocyclic lactones that may be used in the compositions of theinvention include, but are not limited to, the naturally producedavermectins (e.g. including the components designated as A₁a, A₁b, A₂a,A₂b, B₁a, B₁b, B₂a and B₂b) and milbemycin compounds, semisyntheticavermectins and milbemycins, avermectin monosaccharide compounds andavermectin aglycone compounds. Examples of macrocyclic lactone compoundsthat may be used in the compositions include, but are not limited to,abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin,latidectin, lepimectin, selamectin, ML-1,694,554 and milbemycinsincluding, but not limited to, milbemectin, milbemycin D, milbemycin A₃,milbemycin A₄, milbemycin oxime, moxidectin and nemadectin. Alsoincluded are the 5-oxo and 5-oxime derivatives of said avermectins andmilbemycins.

The macrocyclic lactone compounds are known in the art and can easily beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag., or Albers-Schönberg et al. (1981), “Avermectins StructureDetermination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin,“Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may beconsulted. For milbemycins, reference may be made, inter alia, to DaviesH. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins fromAvermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973and EP 0 677 054, both incorporated herein by reference.

The structure of the avermectins and milbemycins are closely related,e.g., by sharing a complex 16-membered macrocyclic lactone ring. Thenatural product avermectins are disclosed in U.S. Pat. No. 4,310,519 andthe 22,23-dihydro avermectin compounds are disclosed in U.S. Pat. No.4,199,569. Mention is also made of U.S. Pat. Nos. 4,468,390, 5,824,653,EP 0 007 812 A1, U.K. Patent Specification 1 390 336, EP 0 002 916, andNew Zealand Patent No. 237 086, inter alia. Naturally occurringmilbemycins are described in U.S. Pat. No. 3,950,360 as well as in thevarious references cited in “The Merck Index” 12^(th) ed., S. Budavari,Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectinis described in the “International Nonproprietary Names forPharmaceutical Substances (INN)”, WHO Drug Information, vol. 17, no. 4,pp. 263-286, (2003). Semisynthetic derivatives of these classes ofcompounds are well known in the art and are described, for example, inU.S. Pat. Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719,4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711,4,978,677, 4,920,148 and EP 0 667 054, all incorporated herein byreference.

In one embodiment, the veterinary compositions of the invention comprisean effective amount of at least one of abamectin, dimadectin,doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin,selamectin, milbemectin, milbemycin D, milbemycin A₃, milbemycin A₄,milbemycin oxime, moxidectin or nemadectin, or a combination thereof. Inanother embodiment, the invention provides a veterinary compositioncomprising an effective amount of at least one of abamectin, emamectin,eprinomectin, ivermectin, doramectin or selamectin, or a combinationthereof. In still another embodiment, which is particularly preferred,the veterinary compositions of the invention comprise an effectiveamount of at least one of ivermectin, eprinomectin, milbemycin oxime ormoxidectin, or a combination thereof.

In another embodiment of the invention, a composition comprising acompound of formula (I) in combination with a class of acaricide orinsecticides known as insect growth regulators (IGRs) are provided.Compounds belonging to this group are well known to the practitioner andrepresent a wide range of different chemical classes. These compoundsall act by interfering with the development or growth of the insectpests. Insect growth regulators are described, for example, in U.S. Pat.Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022or U.K. 2 140 010 as well as U.S. Pat. Nos. 6,096,329 and 6,685,954 (allincorporated herein by reference).

In one embodiment the compositions of the invention may include an IGRcompound that mimics juvenile hormone or that modulates levels ofjuvenile hormones in insects. Examples of juvenile hormone mimicsinclude azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene,methoprene, pyriproxyfen, tetrahydroazadirachtin and4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-one.In another embodiment, the compositions of the invention comprise acompound of formula (I) in combination with methoprene or pyriproxyfenand a pharmaceutically acceptable carrier.

In another embodiment, the compositions of the invention include an IGRcompound that is a chitin synthesis inhibitor. Chitin synthesisinhibitors include chlorofluazuron, cyromazine, diflubenzuron,fluazuron, flucycloxuron, flufenoxuron, hexaflumoron, lufenuron,tebufenozide, teflubenzuron, triflumuron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylureaand 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

In some embodiments, the compositions of the invention may include oneor more antinematodal agents including, but not limited to, activeagents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidinesand the organophosphate class of compounds. In some embodiments,benzimidazoles including, but not limited to, thiabendazole,cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole,fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel,thiophanate and its o,o-dimethyl analogue may be included in thecompositions.

In other embodiments, the compositions of the invention may include animidazothiazole compounds including, but not limited to, tetramisole,levamisole and butamisole.

In still other embodiments, the compositions of the invention mayinclude tetrahydropyrimidine active agents including, but not limitedto, pyrantel, oxantel, and morantel.

Suitable organophosphate active agents include, but are not limited to,coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptenophos,mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

In other embodiments, the compositions may include the antinematodalcompounds phenothiazine, piperazine as the neutral compound and invarious salt forms, diethylcarbamazine, phenols such as disophenol,arsenicals such as arsenide, ethanolamines such as bephenium, theniumclosylate, and methyridine; cyanine dyes including pyrvinium chloride,pyrvinium pamoate and dithiazanine iodide; isothiocyanates includingbitoscanate, suramin sodium, phthalofyne, and various natural productsincluding, but not limited to, hygromycin B, α-santonin and kainic acid.

In other embodiments, the compositions of the invention may includeantitrematodal agents. Suitable antitrematodal agents include, but arenot limited to, the miracils such as miracil D and mirasan;praziquantel, clonazepam and its 3-methyl derivative, oltipraz,lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil,various bisphenol compounds known in the art including hexachlorophene,bithionol, bithionol sulfoxide and menichlopholan; varioussalicylanilide compounds including tribromsalan, oxyclozanide,clioxanide, rafoxanide, nitroxynil, brotianide, bromoxanide andclosantel; triclabendazole, diamfenetide, clorsulon, hetolin andemetine.

Anticestodal compounds may also be advantageously used in thecompositions of the invention including, but not limited to, arecolinein various salt forms, bunamidine, niclosamide, nitroscanate,paromomycin, paromomycin II, praziquantel and epsiprantel. In aparticularly preferred embodiment, the compositions of the invention maycomprise praziquantel.

In yet other embodiments, the compositions of the invention may includeother active agents that are effective against arthropod parasites.Suitable active agents include, but are not limited to, bromocyclen,chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos,bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos,crotoxyphos, cythioate, diazinon, dichlorenthion, diemthoate,dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate,iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos,ronnel, stirofos, benzyl benzoate, carbon disulfide, crotamiton,diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanato acetate,monosulfiram, pirenonylbutoxide, rotenone, triphenyltin acetate,triphenyltin hydroxide, deet, dimethyl phthalate, and the compounds1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde (MGK-11),2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326) and2-(octylthio)ethanol (MGK-874).

In yet another embodiment of the invention, adulticide insecticides andacaricides can also be added to the composition of the invention. Theseinclude pyrethrins (which include cinerin I, cinerin II, jasmolin I,jasmolin II, pyrethrin I, pyrethrin II and mixtures thereof) andsynthetic pyrethroids. Pyrethroids are synthetic analogs of thepyrethrins with increased potency and stability. Pyrethroids that may beused in the compositions of the invention include, but are not limitedto, permethrin, alphacypermethrin, cyfluthrin, beta-cyfluthrin,cyhalothrin, cypermethrin, cyphenothrin, deltamethrin, fenvalerate,flucythrinate, flumethrin, tau-fluvalinate, allethrin, bioallethrin,phenothrin, resmethrin, tetramethrin, transfluthrin and etofenprox.

Carbamate insecticides that may be used in the compositions of theinvention include, but are not limited to, benomyl, carbanolate,carbaryl, carbofuran, methiocarb, metolcarb, promacyl, propoxur,aldicarb, butocarboxim, oxamyl, thiocarboxime and thiofanox.

In another embodiment, an antiparasitic agent that can be included inthe veterinary composition containing a compound of formula (I) can be abiologically active peptide or protein including, but not limited to,depsipeptides other than the compounds of formula (I). These includePF1022A or analogs thereof and emodepside. These compounds act at theneuromuscular junction by stimulating presynaptic receptors belonging tothe secretin receptor family resulting in the paralysis and death ofparasites. In one embodiment of the depsipeptide, the depsipeptide isemodepside (see Wilson et al., Parasitology, January 2003, 126(Pt1):79-86).

In another embodiment, the compositions of the invention may comprise anactive agent from the neonicotinoid class of parasiticides. Theneonicotinoids bind and inhibit insect specific nicotinic acetylcholinereceptors. In one embodiment, the neonicotinoid insecticidal agent thatcan be combined with a compound of formula (I) in a composition of theinvention is imidacloprid. Agents of this class are described, forexample, in U.S. Pat. No. 4,742,060 or in EP 0 892 060 (bothincorporated herein by reference). In another embodiment, thecompositions of the invention may comprise nitenpyram, another activeagent of the neonicotinoid class of pesticides. The use of nitenpyramfor controlling fleas is described in U.S. Pat. No. 5,750,548, which isincorporated herein by reference in its entirety.

In certain other embodiments of the invention, the cyclic depsipeptidesof formula (I) can be combined with the compositions of the invention isa semicarbazone, such as metaflumizone.

In another embodiment, the compositions of the invention mayadvantageously include one or more other isoxazoline compounds known inthe art, including, but not limited to, afoxolaner, sarolaner, lotilanerand fluralaner. This class of active agents are described in U.S. Pat.Nos. 7,964,204, 8,410,153, WO 2014/036056, US 2010/0254960 A1,US2011/0159107, US2012/0309620, US2012/0030841, US2010/0069247, WO2007/125984, WO 2012/086462, U.S. Pat. Nos. 8,318,757, 8,466,115,8,618,126, 8,822,466, 8,383,659, 8,853,186, US 2011/0144349, U.S. Pat.Nos. 8,053,452, 8,952,175, US 2010/0254959, US 2011/152081, WO2007/075459 and US 2009/0133319, WO 2009/025983 and U.S. Pat. No.8,513,431, WO 2009/003075 and US 2010/0173948, WO 2008/150393, WO2008/154528 and U.S. Pat. No. 8,623,875, WO 2010/003877 and U.S. Pat.No. 8,597,688, WO 2010/003923 and U.S. Pat. No. 8,563,474, WO2009/045999 and U.S. Pat. No. 8,367,584, WO 2009/126668 and U.S. Pat.No. 8,546,618, WO 2009/051956, WO 2012/089623, WO 2012/089622, U.S. Pat.No. 8,119,671; U.S. Pat. No. 7,947,715; WO 2102/120135, WO 2012/107533,WO 2011/157748, US 2011/0245274, US 2011/0245239, US 2012/0232026, US2012/0077765, US 2012/0035122, US 2011/0251247, WO 2011/154433, WO2011/154434, US 2012/0238517, US 2011/0166193, WO 2011/104088, WO2011/104087, WO 2011/104089, US 2012/015946, US 2009/0143410, WO2007/123855 A2, US 2011/0118212, U.S. Pat. Nos. 7,951,828 & 7,662,972,US 2010/0137372 A1, US 2010/0179194 A2, US 2011/0086886 A2, US2011/0059988 A1, US 2010/0179195 A1, U.S. Pat. Nos. 7,897,630, and7,951,828, all of which are incorporated herein by reference in theirentirety.

In another embodiment of the invention, nodulisporic acid and itsderivatives may be added to the compositions of the invention. Thesecompounds are used to treat or prevent infections in humans and animalsand are described, for example, in U.S. Pat. Nos. 5,399,582, 5,962,499,6,221,894 and 6,399,786, all of which are hereby incorporated byreference in their entirety. The compositions may include one or more ofthe known nodulisporic acid derivatives in the art, including allstereoisomers, such as those described in the literature cited above.

In another embodiment, anthelmintic compounds of the amino acetonitrileclass (AAD) of compounds such as monepantel (ZOLVIX) and the like may beadded to the compositions of the invention. These compounds aredescribed, for example, in U.S. Pat. No. 7,084,280 to Ducray et al.(incorporated herein by reference); Sager et al., VeterinaryParasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13Mar. 2008, 176-181.

The compositions of the invention may also include aryloazol-2-ylcyanoethylamino compounds such as those described in U.S. Pat. No.8,088,801 to Soll et al., which is incorporated herein by reference, andthioamide derivatives of these compounds, as described in U.S. Pat. No.7,964,621 to Le Hir de Fallois, which is also incorporated herein byreference.

The compositions of the invention may also include paraherquamidecompounds and derivatives of these compounds, including derquantel (seeOstlind et al., Research in Veterinary Science, 1990, 48, 260-61; andOstlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408).The paraherquamide family of compounds is a known class of compoundsthat include a spirodioxepino indole core with activity against certainparasites (see Tett. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380,and J. Antibiotics 1991, 44, 492). In addition, the structurally relatedmarcfortine family of compounds, such as marcfortines A-C, are alsoknown and may be combined with the formulations of the invention (see J.Chem. Soc.—Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Furtherreferences to the paraherquamide derivatives can be found, for example,in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432 andUS 2010/0197624, U.S. Pat. Nos. 5,703,078 and 5,750,695, all of whichare hereby incorporated by reference in their entirety.

In another embodiment of the invention, the compositions may include aspinosyn active agent produced by the soil actinomyceteSaccharopolyspora spinosa (see, for example Salgado V. L. and Sparks T.C., “The Spinosyns: Chemistry, Biochemistry, Mode of Action, andResistance,” in Comprehensive Molecular Insect Science, vol. 6, pp.137-173, 2005) or a semi-synthetic spinosoid active agent. The spinosynsare typically referred to as factors or components A, B, C, D, E, F, G,H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of thesecomponents, or a combination thereof, may be used in the compositions ofthe invention. The spinosyn compound may be a 5,6,5-tricylic ringsystem, fused to a 12-membered macro cyclic lactone, a neutral sugar(rhamnose), and an amino sugar (forosamine). These and other naturalspinosyn compounds, including 21-butenyl spinosyn produced bySaccharopolyspora pagona, which may be used in the compositions of theinvention, may be produced via fermentation by conventional techniquesknown in the art. Other spinosyn compounds that may be used in thecompositions of the invention are disclosed in U.S. Pat. Nos. 5,496,931;5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,840,861;5,670,486; 5,631,155 and 6,001,981, all incorporated by reference hereinin their entirety. The spinosyn compounds may include, but are notlimited to, spinosyn A, spinosyn D, spinosad, spinetoram, orcombinations thereof. Spinosad is a combination of spinosyn A andspinosyn D, and spinetoram is a combination of 3′-ethoxy-5,6-dihydrospinosyn J and 3′-ethoxy spinosyn L.

In general, additional active agents (other than the compound of formula(I) described above) is included in the dosage units of the invention inan amount of between about 0.1 μg and about 1000 mg. Typically, theactive agent may be included in an amount of about 10 μg to about 500mg, about 10 μg to about 400 mg, about 1 mg to about 300 mg, about 10 mgto about 200 mg or about 10 mg to about 100 mg. More typically theadditional active agent will be present in an amount of about 5 mg toabout 50 mg in the compositions of the invention.

The concentration of the additional active agent in the compositions ofthe invention will typically be from about 0.01% to about 30% (w/w)depending on the potency of the active agent. In certain embodiments forvery potent active agents including, but not limited to a macrocycliclactone active agent, the concentration of the active agent willtypically be from about 0.01% to about 10% (w/w), from about 0.01 toabout 1% (w/w), from about 0.01% to about 0.5% (w/w), from about 0.1% toabout 0.5% (w/w) or from about 0.01% to about 0.1% (w/w). In otherembodiments, the concentration of the active agent will typically befrom about 0.1% to about 2% (w/w) or about 0.1% to about 1% (w/w).

In other embodiments, the additional active agent will typically bepresent at higher concentrations to achieve the desired efficacy. Insome embodiments, the active agent will be present in a concentration ofabout 1% to about 30% (w/w), about 1% to about 20% (w/w) or about 1% toabout 15% (w/w). In still other embodiments, the active agent will bepresent in a concentration of about 5% to about 20% (w/w) or about 5% toabout 15% (w/w) in the composition.

In various embodiments of the invention, an additional active agent maybe included in the composition to deliver a dose of about 0.001 mg/kg toabout 50 mg/kg or about 0.5 mg/kg to about 50 mg/kg of body weight ofthe animal. In other embodiments, the active agent will typically bepresent in an amount sufficient to deliver a dose of about 0.05 mg/kg toabout 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg. In other embodiments,the active agent will be present in an amount sufficient to deliver adose of about 0.1 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 1mg/kg or about 0.5 mg/kg to about 50 mg/kg per body weight of theanimal.

In certain embodiments of the invention where the additional activeagent is a very potent compound such as a macrocyclic lactone or otherpotent compounds, the active agent will be present in a concentration toprovide a dose of about 0.001 mg/kg to about 5 mg/kg, about 0.001 mg/kgto about 0.1 mg/kg or about 0.001 mg/kg to about 0.01 mg/kg. In stillother embodiments, the active agent is present in an amount sufficientto deliver a dose of about 0.01 mg/kg to about 2 mg/kg or about 0.1mg/kg to about 1 mg/kg per body weight of the animal. In still otherembodiments, the additional active agent may be present in an amount todeliver a dose of about 1 μg/kg to about 200 μg/kg or about 0.1 mg/kg toabout 1 mg/kg of weight of animal.

In addition to the other active agents mentioned above, combinations oftwo or more active agents may be used with the compounds of theinvention in a composition to treat a desired spectrum of pests andparasites. It would be well within the skill level of the practitionerto decide which individual compound can be used in the inventiveformulation to treat a particular infection of an insect.

The invention will now be further described by way of the followingnon-limiting examples.

EXAMPLES Preparation Examples

The preparation examples below are non-limiting examples of methods usedto prepare the compounds of the invention. The 4-fluoro-N-methyl leucinereagent protected with the tert-butyloxycarbonyl group (BOC) shown belowis used in the preparation of compounds of the invention having a—CH₂C(CH₃)₂F group in the positions corresponding to R¹, R², R³ or R⁴.

This compound is prepared according to standard procedures fromcommercially-available 4-fluoroleucine (Chemical Abstracts RegistryNumber 857026-04-1). It will be appreciated that other groups R¹ to R⁴may also be prepared with different leucine analogs in a similar manner.For example, 3-fluoroleucine (Chemical Abstracts Registry No.171077-98-8, for example see Kaneko et al., Chem. Pharm Bull., 1995,43(5), 760-765) and 5-fluoroleucine (Chemical Abstracts Registry No.159415-71-1, see Moody et al., Tett. Lett., 1994, 35(30), 5485-8) arealso known and could be used to prepare compounds where R¹ to R⁴ aredifferently substituted fluoro leucine residues. In addition, it will beappreciated that alternative amino acids with different side chains mayalso used to prepare alternative compounds of the invention.

N-Boc-L-3-cyclopropylalanine shown below is also used in the preparationof certain compounds of the invention wherein R¹, R², R³ or R⁴ are C1.This compound is known (CAS 89483-06-7) and is commercially available asthe dicyclohexylamine salt.

Benzyl (R)-2-hydroxy-3-(4-morpholinophenyl)propanoate, shown below, isalso used in the preparation of certain compounds of the invention. Thiscompound is known and its preparation is described, for example,Scherkenbeck et al., Eur. J. Org. Chem. 2012, 1546-1553.

Similarly, the compound shown below is used in the preparation of thecompounds of the invention. This compound is known and is described, forexample, in Dutton et al., J. Antibiotics 1994, 47(11), 1322-1327, amongother places.

As shown in Scheme 1 above, the preparation of the compounds of theinvention is conducted by cyclization of the precursor 1-7 afterdeprotection of the terminal amine and carboxylic acid groups. It willbe appreciated by skilled persons in the art that using the generalprocess outlined in Scheme 1 a wide variety of compounds of theinvention may be prepared by selecting the appropriate monomer startingmaterials with the desired groups R¹, R², R³, R⁴, Cy¹ and Cy² in placeand preparing the dimers of general formulae 1-1, 1-2, 1-3 and 1-4 bydeprotection of the appropriate carboxylic acid and amino groups andamide formation.

Preparation Examples 1-16 shown below provide processes for thepreparation of various monomer compounds M1 to M16 substituted with awide variety of groups R¹, R², R³, R⁴, Cy¹ and Cy² that enable thepreparation of a diverse set of dimer compounds used for the preparationof the compounds of the invention.

Preparation Example 1 Preparation of Monomer M1

Experimental Details

(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-cyclopropylpropanoic acid: Intoa 1000-mL 3-necked round-bottom flask, was placed(2S)-2-amino-3-cyclopropylpropanoic acid (10 g, 77.43 mmol, 1.00 equiv),tetrahydrofuran (120 mL), water (120 mL), potassium carbonate (36.7 g,265.54 mmol, 3.40 equiv). This was followed by the addition ofdi-tert-butyl dicarbonate (21.9 g, 100.35 mmol, 0.80 equiv) dropwisewith stirring at 0° C. The resulting solution was stirred for overnightat room temperature. The resulting solution was extracted with 2×60 mLof ether and the aqueous layers combined. and the organic layerscombined. The pH value of the solution was adjusted to 3 with citricacid (2 mmol/L). The resulting solution was extracted with 3×100 mL ofdichloromethane and the organic layers combined and dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 17.2 g(97%) of (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-cyclopropylpropanoicacid as colorless oil. MS (ES, m/z): 228 (M−H).

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid (M1): Into a 1000-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-cyclopropylpropanoic acid (8 g,34.89 mmol, 1.00 equiv), tetrahydrofuran (450 mL). This was followed bythe addition of sodium hydride (2.8 g, 83.33 mmol, 3.00 equiv) dropwisewith stirring at 0° C. To this was added CH3I (40 g, 281.81 mmol, 8.00equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 1.5 h at room temperature. The resulting solution wasallowed to react, with stirring, for an additional overnight at roomtemperature. The reaction was then quenched by the addition of 100 mL ofwater/ice. The resulting solution was extracted with 2×100 mL of MTBEand the aqueous layers combined. The pH value of the solution wasadjusted to 4 with citric acid (2 mol/L). The resulting solution wasextracted with 3×200 mL of ethyl acetate and the organic layers combinedand dried over anhydrous sodium sulfate and concentrated under vacuum.This resulted in 6 g (71%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid as yellow oil. MS (ES, m/z): 242 (M−H);

¹H NMR (DMSO, 300 MHz) δ: 12.59 (brs, 1 H), 4.55-4.29 (m, 1 H), 3.31 (s,3 H), 1.90-1.51 (m, 2 H), 1.47-1.41 (m, 9 H), 0.70-0.50 (m, 1 H),0.50-0.30 (m, 2 H), 0.20-0.00 (m, 2 H).

Preparation Example 2 Preparation of Monomer M2

Experimental Details

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-2-cyclopropylacetic acid(M2): Into a 250-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl]amino]-2-cyclopropylacetic acid (5 g,23.23 mmol, 1.00 equiv), tetrahydrofuran (120 mL). This was followed bythe addition of sodium hydride (1 g, 41.67 mmol, 3.00 equiv) in portionat 0° C. To this was added CH3I (16 g, 112.72 mmol, 8.00 equiv) dropwisewith stirring at 0° C. The resulting solution was stirred for 1 h atroom temperature. The reaction was then quenched by the addition of 20mL of water/ice. The resulting solution was extracted with 2×30 mL ofMTBE and the aqueous layers combined. The pH value of the aqueous phasewas adjusted to 4 with citric acid. The resulting solution was extractedwith 3×80 mL of ethyl acetate and the organic layers combined and driedover anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 3.4 g (64%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-2-cyclopropylacetic acidas yellow oil. MS (ES, m/z): 228 (M−H).

Preparation Example 3 Preparation of Monomer M3

Experimental Details

Tert-butyl(4S)-4-[(E)-2-cyclopropylethenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate:Into a 500-mL 3-necked round-bottom flask was placed tetrahydrofuran(105 mL) under nitrogen atmosphere,(cyclopropylmethyl)triphenylphosphonium (9.1 g, 28.67 mmol, 1.50 equiv).This was followed by the addition of LiHMDS (1M) (23 mL, 23 mmol, 1.50equiv) dropwise with stirring at −78° C. The resulting orange solutionwas warmed-up to room temperature for 1 h then cooled down to −78° C. Tothe above solution was added a solution of tert-butyl(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (3.5 g, 15.27mmol, 1.00 equiv) in THF (20 mL). The resulting solution was stirred for5 h at room temperature. The resulting solution was quenched by theaddition of 105 mL of methanol. The resulting solution was concentratedunder vacuum. The residue was dissolved with 200 mL of ethyl acetate and200 mL of water. The organic phase was collected. The aqueous solutionwas extracted with 2×200 mL of ethyl acetate and the organic layerscombined and dried over sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 2.3 g (56%) oftert-butyl(4S)-4-[(E)-2-cyclopropylethenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylateas light yellow oil. MS (ES, m/z): 268 (M+H).

Tert-butyl(4S)-4-(2-cyclopropylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate:Into a 1000-mL 3-necked round-bottom flask was placed tert-butyl(4S)-4-[(E)-2-cyclopropylethenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(4.5 g, 16.83 mmol, 1.00 equiv) and Tos-NH—NH2 (31.5 g, 168.3 mmol,10.00 equiv) in ethylene glycol dimethyl ether (150 mL). The mixturewarmed to 90° C. was added dropwise a solution of NaOAc (39.4 g, 504.9mmol, 30.00 equiv) in water (400 mL). The resulting solution was stirredfor 4 h at 90° C. After the addition, reaction was cooled down to roomtemperature and extracted with 3×200 mL of ethyl acetate and the organiclayers combined. The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:7). Thisresulted in 1.9 g (42%) of tert-butyl(4S)-4-(2-cyclopropylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylateas yellow oil. MS (ES, m/z): 270 (M+H).

Tert-butyl N-[(2S)-4-cyclopropyl-1-hydroxybutan-2-yl]carbamate: Into a100-mL round-bottom flask, was placed tert-butyl(4S)-4-(2-cyclopropylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.7 g, 6.31 mmol, 1.00 equiv), methanol (34 mL), TsOH (119 mg, 0.69mmol, 0.11 equiv). The resulting solution was stirred for 4 h at roomtemperature. The solids were filtered out. The filtrate was concentratedunder vacuum. The crude product (2.0 g) was purified by Flash-Prep-HPLCwith the following conditions (CombiFlash-1): Column, C18 silica gel;mobile phase, CH3CN:H2O=30/70 increasing to CH3CN:H2O=100:0 within 40min; Detector, UV 220 nm. This resulted in 1.4 g (97%) of tert-butylN-[(2S)-4-cyclopropyl-1-hydroxybutan-2-yl]carbamate as yellow oil. MS(ES, m/z): 230 (M+H).

(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-cyclopropylbutanoic acid: Into a500-mL 3-necked round-bottom flask, was placed tert-butylN-[(2S)-4-cyclopropyl-1-hydroxybutan-2-yl]carbamate (1.2 g, 5.23 mmol,1.00 equiv), chloroform (24 mL), water (36 mL), CH3CN (24 mL), RuCl3(324 mg, 1.57 mmol, 0.30 equiv), NaIO4 (5.6 g, 5.00 equiv). Theresulting solution was stirred for 6 h at room temperature. The reactionwas then quenched by the addition of 500 mL of NaS2O3 (Sat.). Theresulting solution was extracted with 300 mL of MTBE and the aqueouslayers combined. The pH value of the aqueous phase was adjusted to 4with citric acid. The resulting solution was extracted with 3×300 mL ofethyl acetate and the organic layers combined and dried over sodiumsulfate and concentrated under vacuum. This resulted in 2.4 g (crude) of(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-cyclopropylbutanoic acid asblack oil. MS (ES, m/z): 244 (M+H).

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-cyclopropylbutanoic acid(M3): Into a 250-mL 3-necked round-bottom flask, was placedtetrahydrofuran (100 mL),(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-cyclopropylbutanoic acid (2.4 g,9.86 mmol, 1.00 equiv). This was followed by the addition of sodiumhydride (2.37 g, 98.75 mmol, 10.00 equiv) in portion at 0° C. Theresulting solution was stirred 1 h at 0° C. To this was added CH3I (14g, 98.63 mmol, 10.00 equiv) dropwise at 0° C. The resulting solution wasstirred overnight at room temperature. The reaction was then quenched bythe addition of 200 mL of water/ice. The resulting solution wasextracted with 200 mL of MTBE and the aqueous layers combined. The pHvalue of the aqueous phase was adjusted to 4 with citric acid. Theresulting solution was extracted with 3×200 mL of ethyl acetate and theorganic layers combined and dried over sodium sulfate and concentratedunder vacuum. This resulted in 1.5 g (59%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-cyclopropylbutanoic acidas yellow oil. MS (ES, m/z): 258 (M+H).

Preparation Example 4 Preparation of Monomer M4

Experimental Details

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclobutylpropanoic acid(M4): Into a 50-mL round-bottom flask, was placed tetrahydrofuran (200mL), (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-cyclobutylpropanoic acid (2g, 8.22 mmol, 1.00 equiv), CH3I (24 g, 169.09 mmol, 20.57 equiv), sodiumhydride (6.6 g, 275.00 mmol, 33.45 equiv). The resulting solution wasstirred overnight at 38° C. The reaction was then quenched by theaddition of water/ice. The pH value of the solution was adjusted to 4with hydrogen chloride (2 mol/L). The resulting solution was extractedwith 3×20 mL of ethyl acetate and the organic layers combined and driedover anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 1.8 g (85%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclobutylpropanoic acidas colorless oil. MS (ES, m/z): 258 (M+H).

Preparation Example 5 Preparation of Monomer M5

Experimental Details

1-Benzyl 4-methyl (2S)-2-[[(tert-butoxy)carbonyl]amino]butanedioate:Into a 20-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methoxy-4-oxobutanoic acid (150g, 606.69 mmol, 1.00 equiv) in N,N-dimethylformamide (5 L), Cs₂CO₃ (396g, 1.22 mol, 2.00 equiv), BnBr (124 g, 725.02 mmol, 1.20 equiv). Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was diluted with 10 L of EA. The resulting mixturewas washed with 3×5 L of H₂O. The resulting mixture was washed with 3×5L of brine. The mixture was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. This resulted in 170 g (83%) of 1-benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]butanedioate as a white solid. MS(ES, m/z): 338 (M+H).

1-Benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]butanedioate: Into a 10 L3-necked round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of 1-benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]butanedioate (170 g, 503.90 mmol,1.00 equiv) in N,N-dimethylformamide (5 mL), Ag₂O (348 g, 3.00 equiv),CH₃I (1433 g, 10.10 mol, 20.00 equiv). The resulting solution wasstirred for 1 h at 60° C. in an oil bath. The resulting solution wasdiluted with 10 L of EA. The resulting mixture was washed with 3×8 L ofH₂O. The resulting mixture was washed with 3×8 L of brine. The organicphase was dried over anhydrous sodium sulfate. The solids were filteredout. The resulting mixture was concentrated under vacuum. This resultedin 159 g (90%) of 1-benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]butanedioate as yellow oil.MS (ES, m/z): 352 (M+H).

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methoxy-4-oxobutanoicacid: Into a 10-L 3-necked round-bottom flask, was placed a solution of1-benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]butanedioate (159 g) inmethanol (3 L), Palladium carbon (15.9 g, 0.10 equiv), H₂(gas) (enough).The resulting solution was stirred for 2 h at room temperature. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. This resulted in 115 g (97%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methoxy-4-oxobutanoicacid as yellow oil. MS (ES, m/z): 262 (M+H).

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoicacid: Into a 3-L 3-necked round-bottom flask purged and maintained withan inert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methoxy-4-oxobutanoicacid (114 g) in tetrahydrofuran (4 L), CH₃MgBr (874 mL, 6.00 equiv). Theresulting solution was stirred for 3 h at −30° C. in a cold bath. Thereaction was then quenched by the addition of 1000 mL of NH₄Cl/H₂O. ThepH value of the solution was adjusted to 3˜4 with hydrogen chloride/H₂O.The resulting solution was diluted with 6 L of H₂O. The resultingsolution was extracted with 3×4 L of ethyl acetate and the organiclayers combined. The resulting mixture was washed with 2×5 L of brine.The organic phase was dried over anhydrous sodium sulfate. The solidswere filtered out. The resulting mixture was concentrated under vacuum.This resulted in 90 g (crude) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoicacid as yellow oil. MS (ES, m/z): 262 (M+H).

Methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoate:Into a 3-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoicacid (90 g) in dichloromethane (4 L), (diazomethyl)trimethylsilane (340mL, 2.00 equiv, 2M). The resulting solution was stirred for 2 h at roomtemperature in an ice/salt bath. The resulting mixture was washed with2×3 L of H₂O. The resulting mixture was washed with 2×3 L of brine. Theorganic phase was dried over anhydrous sodium sulfate. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Thisresulted in 92 g (crude) of methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoateas yellow oil. MS (ES, m/z): 276 (M+H).

Methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate:Into a 3-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoate(90 g) in dichloromethane (3.0 L), DAST (106 g, 2.00 equiv). Theresulting solution was stirred for 2 h at −30° C. in a cold bath. Thereaction was then quenched by the addition of 1 L of NaHCO₃ at 0° C. Theresulting mixture was washed with 2×1 L of H₂O. The resulting mixturewas washed with 2×1 L of brine. The organic phase was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:100˜1:20). Thisresulted in 15 g (16%) of methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas yellow oil. MS (ES, m/z): 278 (M+H).

(S)-2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoic acid(M5): Into a 500 mL 3-necked round-bottom flask, was placed a solutionof (S)-methyl2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoate (15 g)in MeOH (80 mL), LiOH (11.4 g, 5.00 equiv) in H₂O (150 mL). Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was extracted with 3×100 mL of ethyl acetate. The pHvalue of the water layers was adjusted to 3˜4 with hydrogenchloride/H₂O. The resulting solution was extracted with 3×100 mL ofethyl acetate and the organic layers combined. The resulting mixture waswashed with 2×5 L of brine. The organic phase was dried over anhydroussodium sulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. This resulted in 12.6 g (89%) of(S)-2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoic acidas yellow oil. MS (ES, m/z): 264 (M+H).

Preparation Example 6 Preparation of Monomer M6

Experimental Details

(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid: Into a 2000-mL 4-neckedround-bottom flask, was placed (2R)-2-amino-3-(4-bromophenyl)propanoicacid (150 g, 614.54 mmol, 1.00 equiv), sulfuric acid (0.5M/L) (2500 mL).This was followed by the addition of a solution of NaNO₂ (256 g, 3.71mol, 6.00 equiv) in water (900 mL) dropwise with stirring. The resultingsolution was stirred for 48 h at room temperature. The solids werecollected by filtration. The solid was dried in an oven under reducedpressure. This resulted in 240 g (80%) of(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid as a white solid. MS (ES,m/z): 243 (M−H); ¹H NMR (DMSO, 300 MHz) δ: 12.59 (brs, 1 H), 7.51-7.44(m, 2 H), 7.27-7.14 (m, 2 H), 5.34 (brs, 1 H), 4.16-4.12 (m, 1 H),2.97-2.91 (m, 1 H), 2.80-2.70 (m, 1 H).

Benzyl (2R)-3-(4-bromophenyl)-2-hydroxypropanoate: Into a 2000-mL4-necked round-bottom flask, was placed(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid (60 g, 244.83 mmol, 1.00equiv), potassium carbonate (67.6 g, 489.11 mmol, 2.00 equiv),N,N-dimethylformamide (1000 mL). This was followed by the addition ofBnBr (50.3 g, 294.10 mmol, 1.20 equiv) dropwise with stirring. Theresulting solution was stirred for 1 overnight at room temperature. Theresulting solution was diluted with 2000 mL of H₂O. The resultingsolution was extracted with 3×500 mL of ethyl acetate and the organiclayers combined. The organic layer was washed with 3×500 mL of water and1×500 mL of brine. The organic layers was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 62 g (76%) of benzyl(2R)-3-(4-bromophenyl)-2-hydroxypropanoate as a white solid. ¹H NMR(DMSO, 300 MHz) δ: 7.49 (d, J=3.9 Hz, 2 H), 741-7.34 (m, 5 H), 7.15 (d,J=4.4 Hz, 2 H), 5.28-5.15 (m, 2 H), 4.55-4.51 (m, 1 H), 3.23-3.16 (m, 1H), 3.07-3.01 (m, 1 H).

Benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate: Intoa 2-L 4-necked round-bottom flask, was placed benzyl(2R)-3-(4-bromophenyl)-2-hydroxypropanoate (60 g, 179.00 mmol, 1.00equiv), N,N-dimethylformamide (1000 mL), 1H-imidazole (24.5 g, 359.89mmol, 2.00 equiv). This was followed by the addition of TBDMSCl (32.4 g,1.20 equiv) dropwise with stirring. The resulting solution was stirredfor 16 h at room temperature. The resulting solution was diluted with 2L of H₂O. The resulting solution was extracted with 3×500 mL of ethylacetate and the organic layers combined. The organic layers was washedwith 3×500 mL of brine. The organic layers was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:50). Thisresulted in 78 g (97%) of benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate asyellow oil. MS (ES, m/z): 449 (M+H); ¹H NMR (DMSO, 300 MHz) δ: 7.44 (d,J=4.2 Hz, 2 H), 7.40-7.31 (m, 5 H), 7.16 (d, J=4.0 Hz, 2 H), 5.13 (s, 2H), 4.50-4.46 (m, 1 H), 3.03-2.98 (m, 1 H), 2.86-2.79 (m, 1 H), 0.73 (s,9 H), −0.15 (s, 3 H), −0.25 (s, 3 H).

Benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(morpholin-4-yl)phenyl]propanoate:Into a 2-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (78 g,173.54 mmol, 1.00 equiv), X-phos (8.27 g, 0.10 equiv), Pd(OAc)₂ (1.95 g,8.69 mmol, 0.05 equiv), toluene (1500 mL), morpholine (45.3 g, 519.97mmol, 3.00 equiv), CsCO₃ (170 g, 3.00 equiv). The resulting solution wasstirred for 16 h at 90° C. The solids were filtered out. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:5). This resulted in 64 g (81%) of benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(morpholin-4-yl)phenyl]propanoateas yellow oil. MS (ES, m/z): 456 (M+H); ¹H NMR (CDCl3, 300 MHz) δ:7.34-7.31 (m, 5 H), 7.12 (d, J=4.2 Hz, 2 H), 6.90-6.80 (m, 2 H),5.20-5.10 (m, 2 H), 4.36-4.32 (m, 1 H), 3.90-3.80 (m, 4 H), 3.13-3.05(m, 4 H), 3.04-2.95 (m, 1 H), 2.89-2.82 (m, 1 H), 0.79 (s, 9 H), −0.15(s, 3 H), −0.20 (s, 3 H).

Benzyl (2R)-2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate (M6): Intoa 2000-mL 4-necked round-bottom flask, was placed benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(morpholin-4-yl)phenyl]propanoate(60 g, 131.68 mmol, 1.00 equiv), tetrahydrofuran (1200 mL). This wasfollowed by the addition of TBAF (51.7 g, 197.74 mmol, 1.20 equiv), inportions at 0° C. The resulting solution was stirred for 20 min at roomtemperature. The resulting solution was diluted with 2000 mL of H₂O. Theresulting solution was extracted with 3×500 mL of ethyl acetate and theorganic layers combined. The organic layers was washed with 3×500 mL ofwater and 1×500 mL of brine. The organic layers was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 42 g (93%) of benzyl(2R)-2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate as a yellow solid.MS (ES, m/z): 342 (M+H); ¹H NMR (DMSO, 300 MHz) δ: 7.40-7.27 (m, 5H),7.06 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.57 (d, J=6.3 Hz, 1H),5.08(s, 2H), 4.27-4.21(m, 1H), 3.75-3.71(m, 4H), 3.06-3.03(m, 4H),2.91-2.74(m, 2H).

Preparation Example 7 Preparation of Monomer M7

Experimental Details

4-(5-bromopyridin-2-yl)morpholine: Into a 1-L round-bottom flask, wasplaced a solution of 5-bromo-2-chloropyridine (50 g, 259.82 mmol, 1.00equiv) in N,N-dimethylformamide (300 mL), morpholine (91 g, 1.04 mol,4.00 equiv), potassium carbonate (108 g, 781.42 mmol, 3.00 equiv). Theresulting solution was stirred overnight at 120° C. The resultingsolution was extracted with 5×150 mL of ethyl acetate and the organiclayers combined. The resulting mixture was washed with 3×100 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The resulting mixture was washed withPE:EA=1:5. This resulted in 80 g (63%) of4-(5-bromopyridin-2-yl)morpholine as a white solid. MS (ES, m/z): 243(M+H); ¹H NMR (CDCl3, 300 MHz) δ: 8.22 (s, 1 H), 7.57 (d, J=4.5 Hz, 1H), 6.54 (d, J=2.4 Hz, 1 H), 3.82 (t, J=5.1 Hz, 4 H), 3.48 (t, J=5.1 Hz,4 H).

methyl (2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate: Into a250-mL round-bottom flask and maintained with an inert atmosphere ofnitrogen, was placed a solution of 4-(5-bromopyridin-2-yl)morpholine (5g, 20.57 mmol, 1.00 equiv) in N,N-dimethylformamide (120 mL), methylprop-2-enoate (3.54 g, 41.12 mmol, 2.00 equiv), Pd(OAc)2 (92 mg, 0.41mmol, 0.02 equiv), sodium bicarbonate (3.46 g, 41.19 mmol, 2.00 equiv),Bu4NCl (11.4 g, 41.02 mmol, 2.00 equiv). The resulting solution wasstirred for 3 days at 100° C. The resulting solution was extracted with5×150 mL of ethyl acetate and the organic layers combined. The resultingmixture was washed with 3×100 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The solids werefiltered out. This resulted in 11.5 g (56%) of methyl(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate as a light brownsolid. MS (ES, m/z): 249 (M+H); ¹H NMR (CDCl3, 300 MHz) δ: 8.30 (s, 1H), 7.72-7.58 (m, 2 H), 6.64 (d, J=4.5 Hz, 1H), 6.27 (d, J=8.0 Hz, 1 H),3.84-3.80 (m, 7 H), 3.62 (t, J=4.8 Hz, 4 H).

(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoic acid: Into a 500-mLround-bottom flask, was placed a solution of methyl(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate (11 g, 44.31 mmol,1.00 equiv) in methanol/H2O (60:60 mL), LiOH (10.6 g, 442.59 mmol, 10.00equiv). The resulting solution was stirred for 1 h at 80° C. Theresulting solution was diluted with 150 ml of water. The pH value of thesolution was adjusted to 6˜7 with NaHCO3(Sat.). The resulting solutionwas extracted with 5×150 mL of ethyl acetate and the organic layerscombined. The organic phase was washed with 3×150 mL of brine. Theorganic phase was dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 10.4 g (crude) of(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoic acid as a lightbrown solid. MS (ES, m/z): 245 (M+H).

benzyl (2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate: Into a250-mL round-bottom flask, was placed a solution of(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoic acid (4 g, 17.08mmol, 1.00 equiv) in N,N-dimethylformamide (70 mL), potassium carbonate(7.1 g, 51.37 mmol, 3.00 equiv), (bromomethyl)benzene (4.4 g, 25.73mmol, 1.50 equiv). The resulting solution was stirred overnight at roomtemperature. The resulting solution was extracted with 5×150 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×150 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The resulting mixture waswashed with 1×70 mL of PE. The solids were collected by filtration. Thisresulted in 10 g (72%) of benzyl(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate as a yellow solid.MS (ES, m/z): 325 (M+H); ¹H NMR (CDCl3, 300 MHz) δ: 8.30 (s, 1 H),7.70-7.62 (m, 2 H), 7.45-7.32 (m, 5 H), 6.63 (d, J=4.5 Hz, 1 H), 6.32(d, J=8.0 Hz, 1 H), 5.25 (s, 2 H), 3.82 (t, J=4.5 Hz, 4 H), 3.63-3.60(m, 4 H).

(2R,3S)-2,3-dihydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate: Intoa 100-mL 3-necked round-bottom flask, was placed tert-Butanol:H2O (20:20mL), AD-MIX (8.6 g), This was followed by addition of benzyl(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate (2 g, 6.17 mmol,1.00 equiv) and MeSO2NH2 (586 g, 6.17 mol, 1.00 equiv) with stirring at0° C. The resulting solution was stirred for 3 days at room temperature.The reaction was then quenched by the addition of Na2SO3. The resultingsolution was extracted with 3×150 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:1). This resulted in 5.4 g (49%) ofbenzyl(2R,3S)-2,3-dihydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate as alight yellow solid. MS (ES, m/z): 359 (M+H).

benzyl (2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate (M7):Into a 100-mL round-bottom flask, was placed a solution of benzyl(2R,3S)-2,3-dihydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate (1.5g, 4.19 mmol, 1.00 equiv) in dichloromethane (15 mL), trifluoroaceticacid (5 mL), Et3SiH (10 mL). The resulting solution was stirred for 3days at 50° C. The resulting mixture was concentrated under vacuum. Thereaction was then quenched by the addition of water/ice. The pH value ofthe solution was adjusted to 9 with sodium bicarbonate aq. The resultingsolution was extracted with 3×40 mL of dichloromethane and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:2). This resulted in 2.3 g (27%) ofbenzyl (2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate asyellow oil. MS (ES, m/z): 343 (M+H); ¹H NMR (CDCl3, 300 MHz) δ: 8.02 (s,1 H), 7.43-7.32 (m, 6 H), 6.54 (d, J=4.4 Hz, 1 H), 5.21 (s, 2 H),4.52-4.46 (m, 1 H), 3.84 (t, J=7.8 Hz, 4 H), 3.48 (t, J=4.8 Hz, 4 H)3.05-3.01 (m, 1H), 2.91-2.85 (m, 1H).

Preparation Example 8 Preparation of Monomer M8

Experimental Details

(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid: Into a 5-L 4-neckedround-bottom flask, was placed sulfuric acid/H2O (0.5 mol/L)(3.2 L),(2R)-2-amino-3-(4-bromophenyl)propanoic acid (100 g, 409.69 mmol, 1.00equiv). This was followed by the addition of a solution of NaNO2 (350 g,5.07 mol, 12.38 equiv) in H2O (500 mL) dropwise with stirring at 0° C.The resulting solution was stirred overnight at room temperature. Thesolids were collected by filtration. The solid was dried in an ovenunder reduced pressure. This resulted in 146 g (73%) of(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid as a white solid. MS (ES,m/z): 243 (M−H).

(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoic acid:Into a 1-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed dioxane (500 mL), H₂O (50 mL),(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid (30 g, 122.41 mmol, 1.00equiv),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(40 g, 190.41 mmol, 1.60 equiv), K3PO4 (65 g, 306.21 mmol, 2.50 equiv),Pd(dppf)Cl2 (4.5 g, 6.15 mmol, 0.05 equiv). The resulting solution wasstirred for 2 h at 75° C. in an oil bath. The reaction mixture wascooled. The resulting mixture was concentrated under vacuum. The residuewas dissolved in 100 mL of ether. The solids were filtered out. Thesolids were dissolved in 10 mL of H₂O and 500 mL of THF. The pH value ofthe solution was adjusted to 4-5 with hydrogen chloride (12 mol/L). Thesolids were filtered out. The filtrate was dried over anhydrous sodiumsulfate and concentrated under vacuum. This resulted in 28 g (92%) of(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoic acid asa light brown solid. MS (ES, m/z): 249 (M+H).

Benzyl (2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate(M8): Into a 500-mL round-bottom flask, was placed toluene (300 mL),(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoic acid (9g, 36.25 mmol, 1.00 equiv), phenylmethanol (10.3 g, 95.25 mmol, 2.50equiv), TsOH (2 g, 11.61 mmol, 0.30 equiv), 4A-MS (5.4 g). The resultingsolution was stirred for 40 min at 110° C. in an oil bath. The reactionmixture was cooled. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10-1:3). This resulted in24 g (98%) of benzyl(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate as awhite solid. MS (ES, m/z): 339 (M+H); ¹HNMR(300 MHz, CDCl₃, ppm): δ7.62-7.30(m, 7H), 7.13(d, J=8.4 Hz, 2H), 6.12-6.10(m, 1H), 5.24(s, 2H),4.52-4.48(m, 1H), 4.35-4.32(m,2H), 3.96-3.92(m,2H), 3.16-2.95(m, 2H),2.67-2.49(m,2H).

Preparation Example 9 Preparation of Monomer M9

Experimental Details

(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoic acid: Into a 2000-mL3-necked round-bottom flask, was placed a solution of(2R)-2-amino-3-(4-tert-butylphenyl)propanoic acid (30 g, 135.57 mmol,1.00 equiv) in sulfuric acid(0.5M) (480 mL), a solution of NaNO2 (94 g,1.36 mol, 10.00 equiv) in water(180 mL). The resulting solution wasstirred overnight at room temperature in an ice/salt bath. The solidswere collected by filtration. This resulted in 20.0 g (66%) of(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoic acid as a white solid. MS(ES, m/z): 221 (M−H).

(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate (M9): Into a 2000-mL3-necked round-bottom flask, was placed a solution of(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoic acid (40 g, 179.95 mmol,1.00 equiv) in N,N-dimethylformamide (1000 mL), potassium carbonate (50g, 361.77 mmol, 2.00 equiv), BnBr (61 g, 356.66 mmol, 2.00 equiv). Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was diluted with 2000 mL of EA. The resulting mixturewas washed with 3×2000 mL of H2O. The resulting mixture was washed with2×2000 mL of Brine. The mixture was dried over anhydrous sodium sulfate.The solids were filtered out. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:50˜1:10). This resulted in 42 g (75%)of benzyl (2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate as yellow oil.¹HNMR (300 MHz,CDCl₃, ppm): δ 7.40-7.27 (m, 7H), 7.10 (d, J=8.1 Hz, 2H),5.20 (s, 2H), 4.49 (t, J=5.4 Hz, 1H), 3.14-2.93 (m, 2H), 1.31 (s, 9H).

Preparation Example 10 Preparation of Monomer M10

Experimental Details

2-Hydroxy-3-[4-(trifluoromethyl)phenyl]propanoic acid: Into a 500-mL3-necked round-bottom flask, was placed2-amino-3-[4-(trifluoromethyl)phenyl]propanoic acid (20 g, 85.77 mmol,1.00 equiv), sulfuric acid (0.5 M) (340 mL). This was followed by theaddition of a solution of NaNO₂ (35.5 g, 514.49 mmol, 6.00 equiv) inwater (80 mL) dropwise with stirring at 0° C. The resulting solution wasstirred for 1 h at 0° C. The resulting solution was allowed to react,with stirring, overnight at room temperature. The solids were collectedby filtration. This resulted in 17.5 g (87%) of2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoic acid as a white solid.MS (ES, m/z): 233 (M−H); ¹H NMR (DMSO, 300 MHz) δ: 7.63 (d, J=3.9 Hz, 2H), 7.46 (d, J=4.0 Hz, 2 H), 4.21-4.17 (m, 1 H), 3.09-3.03 (m, 1 H),2.91-2.84 (m, 1 H).

Benzyl (2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate (M10):Into a 500-mL 3-necked round-bottom flask, was placed(2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoic acid (17.5 g,74.73 mmol, 1.00 equiv), (bromomethyl)benzene (15.3 g, 89.46 mmol, 1.20equiv), potassium carbonate (31 g, 224.30 mmol, 3.00 equiv),N,N-dimethylformamide (100 mL). The resulting solution was stirred for30 min at 0° C. and allowed to reach room temperature with stirringovernight. The reaction was then quenched by the addition of 250 mL ofwater. The resulting solution was extracted with 3×150 mL of ethylacetate and the organic layers were combined. The resulting mixture waswashed with 3×250 mL of brine. The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified on a silica gel column with ethyl acetate/petroleum ether (1:6)to give 10.6 g (44%) of benzyl(2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate as a white solid.¹H NMR (DMSO, 300 MHz) δ: 7.60 (d, J=4.0 Hz, 2 H), 7.42 (d, J=4.0 Hz, 2H), 7.39-7.27 (m, 5 H), 5.72 (d, J=3 Hz, 1 H), 5.10 (s, 2 H), 4.40-4.33(m, 1 H), 3.10-3.04 (m, 1 H), 2.99-2.91 (m, 1 H).

Preparation Example 11 Preparation of Monomer M11

Experimental Details

4-(4-Bromo-2-fluorophenyl)morpholine: Into a 1-L round-bottom flaskpurged and maintained with an inert atmosphere of nitrogen, was placed asolution of 4-bromo-2-fluoro-1-iodobenzene (15 g, 49.85 mmol, 1.00equiv) in toluene (300 mL). Pd₂(dba)₃ (1.3 g, 1.42 mmol, 0.03 equiv).Cs2CO3 (41 g, 125.45 mmol, 2.50 equiv). XantPhos (2.9 g, 5.01 mmol, 0.10equiv). morpholine (4.3 g, 49.36 mmol, 1.00 equiv). The resultingsolution was stirred overnight at 100° C. The reaction was then quenchedby the addition of 150 mL of water. The resulting solution was extractedwith 3×100 mL of ethyl acetate and the organic layers combined and driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:15). This resulted in 10.5 g (81%) of4-(4-bromo-2-fluorophenyl)morpholine as a yellow solid. MS (ES, m/z):260 (M+H).

Benzyl (2E)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]prop-2-enoate: Into a100-mL round-bottom flask purged and maintained with an inert atmosphereof nitrogen, was placed 4-(4-bromo-2-fluorophenyl)morpholine (1.25 g,4.81 mmol, 1.00 equiv). Pd(OAc)2 (50 mg, 0.22 mmol, 0.05 equiv). asolution of sodium bicarbonate (810 mg, 9.64 mmol, 2.00 equiv) inN,N-dimethylformamide (30 mL). Bu4NCl (2.7 g, 9.72 mmol, 2.00 equiv).benzyl prop-2-enoate (1.6 g, 9.87 mmol, 2.00 equiv). The resultingsolution was stirred for 36 h at 100° C. The reaction was then quenchedby the addition of water. The resulting solution was extracted with4×100 mL of ethyl acetate and the organic layers combined. The organicphase was washed with 3×60 mL of brine. The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:5). This resulted in 10.5 g (80%) of benzyl(2E)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]prop-2-enoate as a yellowsolid. MS (ES, m/z): 342 (M+H).

Benzyl(2R,3S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2,3-dihydroxypropanoate:Into a 250-mL 3-necked round-bottom flask, was placed a solution ofAD-mix (12.3 g) in tert-Butanol/H2O (60:60 mL). This was followed by theaddition of benzyl(2E)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]prop-2-enoate (3 g, 8.79 mmol,1.00 equiv), in portions at 0° C. To this was added MeSO2NH2 (1.23 g,1.00 equiv), in portions at 0° C. The resulting solution was stirred for3 days at room temperature. The reaction was then quenched by theaddition of Na2SO3. The resulting solution was extracted with 3×100 mLof ethyl acetate and the organic layers combined. The organic phase waswashed with 3×60 mL of brine. The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 9.5 g (72%) of benzyl(2R,3S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2,3-dihydroxypropanoate asyellow oil. MS (ES, m/z): 376 (M+H).

Benzyl (2R)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-hydroxypropanoate(M11): Into a 40-mL vial, was placed a solution of benzyl(2R,3S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2,3-dihydroxypropanoate(900 mg, 2.40 mmol, 1.00 equiv) in dichloromethane (2 mL), Et3 SiH (4mL)., trifluoroacetic acid (2 mL). The resulting solution was stirredfor 3 days at room temperature. The reaction was then quenched by theaddition of water/ice. The resulting solution was extracted with 3×80 mLof ethyl acetate and the organic layers combined. The organic phase waswashed with 3×60 mL of brine. The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 4.1 g (48%) of benzyl(2R)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-hydroxypropanoate asreddish oil. MS (ES, m/z): 360 (M+H).

Preparation Example 12 Preparation of Monomer M12

Experimental Details

(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoicacid: Into a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed dioxane/H₂O (88 mL),(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid (4 g, 16.32 mmol, 1.00equiv),2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(4.0 g, 16.39 mmol, 1.00 equiv), Pd(dppf)Cl₂ (640 mg, 0.87 mmol, 0.05equiv), K₃PO₄ (11 g, 51.82 mmol, 3.00 equiv). The resulting solution wasstirred for 4 h at 80° C. in an oil bath. The reaction mixture wascooled. The resulting mixture was concentrated under vacuum. The residuewas dissolved in 50 mL of ether. The solids were collected byfiltration. The solids were dissolved in 50 mL of THF. The pH value ofthe solution was adjusted to 5 with hydrogen chloride (12 mol/L). Theresulting solution was diluted with 200 mL of ethyl acetate. The solidswere collected by filtration. The filtrate was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 4.5 g(98%) of(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoicacid as light yellow oil. MS (ES, m/z): 281 (M−H).

Benzyl(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate(M12): Into a 500-mL round-bottom flask, was placed toluene (200 mL),(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoicacid (4.5 g, 15.94 mmol, 1.00 equiv), BnOH (2.24 g, 1.30 equiv), TsOH(540 mg, 3.14 mmol, 0.20 equiv), 4A-MS (2 g). The resulting solution wasstirred for 4 h at 110° C. in an oil bath. The reaction mixture wascooled. The solids were filtered out. The filtrate mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:20-1:10). This resulted in5 g (84%) of benzyl(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate asa light yellow solid. ¹HNMR(300 MHz,CDCl3, ppm): δ 7.62-7.30(m, 7H),7.11(d, J=8.4 Hz, 2H), 5.89(br, 1H), 5.21(s,2H), 4.52-4.48(m,1H),3.16-2.95(m,2H), 2.71-2.67(m,4H), 2.25-2.12(m,2H).

Preparation Example 13 Preparation of Monomer M13

Experimental Details

(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoic acid: Into a1000-mL 3-necked round-bottom flask, was placed(2R)-2-amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride(10 g, 35.01 mmol, 1.00 equiv). This was followed by the addition of asolution of NaNO2 (29 g, 420.29 mmol, 12.00 equiv) in water (150 mL)dropwise with stirring at 0° C. To this was added sulfuric acid (0.5M/L)(300 mL). The resulting solution was stirred overnight at roomtemperature. The resulting solution was extracted with 3×200 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×200 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 11 g(crude) of (2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoic acidas yellow oil. MS (ES, m/z): 249 (M−H).

benzyl (2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate (M13):Into a 1000-mL 3-necked round-bottom flask, was placed(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoic acid (11 g, 43.97mmol, 1.00 equiv), N,N-dimethylformamide (300 mL), potassium carbonate(12 g, 86.82 mmol, 2.00 equiv). This was followed by the addition of(bromomethyl)benzene (9 g, 52.62 mmol, 1.20 equiv) dropwise withstirring at 0° C. The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by the addition of 100 mL ofwater. The resulting solution was extracted with 3×150 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×200 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 7.6 g(51%) of benzyl (2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoateas yellow oil. ¹H NMR (DMSO, 300 MHz) δ: 7.45-7.30 (m, 7 H), 7.25-7.17(m, 2 H), 5.70 (d, J=2.7 Hz, 1 H), 5.10 (s, 2 H), 4.34-4.32 (m, 1 H),3.04-2.98 (m, 1 H), 2.92-2.85 (m, 1 H).

Preparation Example 14 Preparation of Monomer M14

Experimental Details

Benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]propanoate:Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (14.53g, 32.33 mmol, 1.00 equiv), 4,4-difluoropiperidine (6.2 g, 51.19 mmol,1.20 equiv), CsCO3 (19 g, 3.00 equiv), X-PhOS (309 mg, 0.02 equiv), Tol(50 mL), Pd(OAc)2 (145 mg, 0.65 mmol, 0.02 equiv). The resultingsolution was stirred for 16 h at 90° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:6). This resulted in 12.28g (78%) of benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]propanoateas colorless oil.

Benzyl (2R)-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]-2-hydroxypropanoate(M14): Into a 100-mL 3-necked round-bottom flask, was placed benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]propanoate(12.28 g, 25.08 mmol, 1.00 equiv), tetrahydrofuran (30 mL), TBAF (8.4 g,32.13 mmol, 1.20 equiv). The resulting solution was stirred for 20 minat room temperature. The resulting mixture was concentrated undervacuum. The resulting solution was diluted with 100 mL of ethyl acetate.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 6.8 g (72%) of benzyl(2R)-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]-2-hydroxypropanoate as awhite solid. MS (ES, m/z): 376 (M+H).

Preparation Example 15 Preparation of Monomer M15

Experimental Details

tert-butyl(2S)-3-(4-bromo-3-fluorophenyl)-2-[(diphenylmethylidene)amino]propanoate:Into a 1000-mL 3-necked round-bottom flask, was placed tert-butyl2-[(diphenylmethylidene)amino]acetate (30 g, 101.57 mmol, 1.00 equiv),toluene (315 mL), a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene(54 g, 201.55 mmol, 1.98 equiv) in chloroform (135 mL),O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (1.1 g, 2.09 mmol,0.02 equiv), potassium hydroxide (56 g, 998.04 mmol, 9.83 equiv). Theresulting solution was stirred for 3 days at −20° C. The resultingsolution was diluted with 1000 mL of EA. The resulting mixture waswashed with 3×1000 mL of H2O. The organic layer was dried over sodiumsulfate. The solids were filtered out. The filtrate was concentratedunder vacuum. The residue was applied onto a C18 reversed phase columnwith H2O/ACN (1/9). This resulted in 28 g (57%) of tert-butyl(2S)-3-(4-bromo-3-fluorophenyl)-2-[(diphenylmethylidene)amino]propanoateas light yellow oil. MS (ES, m/z): 482 (M+H).

tert-butyl (2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoate: Into a 2-L3-necked round-bottom flask, was placed tert-butyl(2S)-3-(4-bromo-3-fluorophenyl)-2-[(diphenylmethylidene)amino]propanoate(28 g, 58.04 mmol, 1.00 equiv), tetrahydrofuran (580 mL), Citric Acid(580 mL). The resulting solution was stirred for 4 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with 1000 mL of water. The resultingsolution was extracted with 3×200 mL of ether and the aqueous layerscombined. The pH value of the aqueous layer was adjusted to 8 withsodium bicarbonate and extracted with 3×300 mL of ethyl acetate. Theorganic layers combined and dried over sodium sulfate and concentratedunder vacuum. This resulted in 14.8 g (80%) of tert-butyl(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoate as light yellow oil.MS (ES, m/z): 318 (M+H).

(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoic acid: Into a 500-mLround-bottom flask, was placed tert-butyl(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoate (5.9 g, 18.54 mmol,1.00 equiv), dichloromethane (200 mL), trifluoroacetic acid (21 g,185.77 mmol, 10.02 equiv). The resulting solution was stirred for 3 daysat room temperature. The resulting mixture was concentrated undervacuum. The residue was applied onto a C18 reversed phase column withH2O/ACN (1/3). This resulted in 5.4 g (crude) of(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoic acid as a white solid.MS (ES, m/z): 262 (M+H).

(2S)-3-(4-bromo-3-fluorophenyl)-2-hydroxypropanoic acid: Into a 500-mL3-necked round-bottom flask, was placed(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoic acid (5.4 g, 20.60mmol, 1.00 equiv), trifluoroacetic acid (28.3 g, 250.35 mmol, 12.15equiv), water (180 mL), to the above was added a solution of NaNO2 (17.1g, 247.83 mmol, 12.03 equiv) in water (180 mL) slowly. The resultingsolution was stirred for 16 h at room temperature. The solids werecollected by filtration. This resulted in 3.1 g (57%) of(2S)-3-(4-bromo-3-fluorophenyl)-2-hydroxypropanoic acid as a lightyellow solid.

(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoicacid: Into a 500-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed(2S)-3-(4-bromo-3-fluorophenyl)-2-hydroxypropanoic acid (3 g, 11.40mmol, 1.00 equiv),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(4.8 g, 22.85 mmol, 2.00 equiv), K3PO4 (7.28 g, 34.30 mmol, 3.01 equiv),dioxane (180 mL), water (18 mL), Pd(dppf)Cl2 (1.67 g, 2.28 mmol, 0.20equiv). The resulting solution was stirred for 5 h at 80° C. Theresulting mixture was concentrated under vacuum. The resulting mixturewas diluted with 900 mL of ether. The solids were collected byfiltration. The solids were dissolved in 200 mL of tetrahydrofuran. ThepH value of the solution was adjusted to 3-4 with hydrogen chloride. Thesolid was filtered out. The filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1/10). This resulted in 2.63 g (87%) of(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoicacid as brown solid. MS (ES, m/z): 265 (M−H).

Benzyl(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoate(M15): Into a 100-mL round-bottom flask, was placed(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoicacid (1 g, 3.76 mmol, 1.00 equiv), BnOH (1.1 g), TsOH (160 mg, 0.93mmol, 0.25 equiv), 4A-Ms (1 g), toluene (20 mL). The resulting solutionwas stirred for 4 h at 110° C. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1/4). This resulted in 350 mg (26%) ofbenzyl(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoateas brown oil. ¹HNMR(300 MHz,CD₃OD, ppm): δ 7.37-7.29 (m,5H),7.20-7.15(m,1H), 6.97-6.92(m,2H), 6.02 (br, 1H), 5.19 (s,2H), 4.44-4.40(m, 1H), 4.30-4.27(m,2H), 3.92-3.885 (m,2H), 3.33-2.90(m, 2H), 2.47-2.46(m,2H).

Preparation Example 16 Preparation of Monomer M16

Experimental Details

1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropane-1-carboxylic acid(M16): Into a 100-mL round-bottom flask, was placed1-[[(tert-butoxy)carbonyl]amino]cyclopropane-1-carboxylic acid (2 g,9.94 mmol, 1.00 equiv), tetrahydrofuran (30 mL). This was followed bythe addition of MeI (5 mL, 8.00 equiv) at 0° C. in 10 min. To this wasadded sodium hydride (1.32 g, 55.00 mmol, 5.50 equiv) in portions at 0°C. in 10 min. The resulting solution was stirred for 24 h at roomtemperature. The reaction was slowly poured into 150 mL of water at 0°C. The resulting solution was washed with 30 mL of ether. The aqueoussolution was collected and the pH value was adjusted to 3 with citricacid (1 mol/L). The resulting solution was extracted with 3×40 mL ofethyl acetate and the organic layers combined and concentrated undervacuum. This resulted in 2.5 g (crude) of1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropane-1-carboxylic acidas a yellow solid. MS (ES, m/z): 216 (M+H).

Preparation Examples 17-32 shown below provide processes for thepreparation of various dimer compounds D1 to D16 substituted with a widevariety of groups R¹, R², R³, R⁴, Cy¹ and Cy² that enable thepreparation of a diverse set of dimer compounds used for the preparationof the compounds of the invention.

Preparation Example 17 Preparation of Dimer D1

(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D1): Into a 250-mL 3-necked round-bottom flask, was placed benzyl(2R)-2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate (2.8 g, 8.20 mmol,1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-cyclopropylpropanoic acid (2 g,8.72 mmol, 1.00 equiv), dichloromethane (80 mL). This was followed bythe addition of DCC (1.9 g, 9.21 mmol, 1.10 equiv),4-dimethylaminopyridine (1.1 g, 9.00 mmol, 1.10 equiv) and HOBt (1.2 g,8.88 mmol, 1.10 equiv) in portions with stirring at 0° C. The resultingsolution was stirred for 1 overnight at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:5). This resulted in 4.2 g (90%) of(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate asa yellow solid. MS (ES, m/z): 567 (M+H).

Preparation Example 18 Preparation of Dimer D2

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate (D2):Into a 2-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tetrahydrofuran (1.5 L),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (50g, 203.82 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (36.7 g,203.66 mmol, 1.00 equiv), triphenylphosphine (85 g, 324.07 mmol, 1.50equiv). This was followed by the addition of DEAD (56.5 g, 324.43 mmol,1.20 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:50-1:10). This resulted in82 g (99%) of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as pinkoil. MS (ES, m/z): 408 (M+H); 1HNMR (300 MHz, CDCl3, ppm): δ7.41-7.31(m, 5H), 5.31-5.10 (m, 3H), 5.01-4.73 (m, 1H), 2.77-2.74 (m, 3H),1.72-1.65 (m, 2H), 1.60-1.58 (m, 1H), 1.52-1.50 (m, 3H), 1.47 (s, 9H),0.96-0.94 (m, 6H).

Preparation Example 19 Preparation of Dimer D3

(2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D3): Into a 100-mL round-bottom flask, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid (700 mg, 2.88 mmol, 1.00 equiv) in dichloromethane (20 mL), benzyl(2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate (1 g, 2.92mmol, 1.00 equiv). This was followed by the addition of DCC (660 mg,3.20 mmol, 1.10 equiv), in portions at 0° C. To this was added4-dimethylaminopyridine (400 mg, 3.27 mmol, 1.10 equiv), in portions at0° C. To the mixture was added HOBT (440 mg, 3.26 mmol, 1.10 equiv), inportions at 0° C. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:3). This resulted in 1 g (61%) of(2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate asa white solid. MS (ESI, m/z): 568 [M+H]+.

Preparation Example 20 Preparation of Dimer D4

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D4): Into a 1000-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (15 g, 56.97 mmol, 1.00 equiv) in dichloromethane (400 mL), benzyl(2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate (12 g, 37.00mmol, 1.00 equiv). This was followed by the addition of HOBT (7.5 g,55.51 mmol, 1.20 equiv), DCC (11 g, 53.31 mmol, 1.20 equiv) and4-dimethylaminopyridine (6.8 g, 55.66 mmol, 1.20 equiv) respectively inportions with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:10). This resulted in 21 g (65%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas red oil. MS (ES, m/z): 570 (M+H).

Preparation Example 21 Preparation of Dimer D5

(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D5): Into a 100-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed dichloromethane (10 mL,1.10 equiv), benzyl(2R)-2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate (130 mg, 0.38mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (100 mg, 0.38 mmol, 1.00 equiv). This was followed by the additionof HOBT (57 mg, 0.42 mmol, 1.10 equiv), DCC (86 mg, 0.42 mmol, 1.10equiv) and 4-dimethylaminopyridine (51 mg, 0.42 mmol, 1.10 equiv)respectively in portions with stirring at 0° C. The resulting solutionwas stirred overnight at room temperature. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 180 mg (80.5%) of(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas a light yellow solid. MS (ES, m/z): 587 (M+H); ¹HNMR (300 MHz, CDCl₃,ppm): δ 7.38-7.36 (m, 4H), 7.29-7.25 (m, 1H), 7.20-6.99 (m, 4H),5.27-5.18 (m, 1H), 5.18-5.09 (m, 2H), 5.08-4.83 (m, 1H), 4.01 (br, 4H),3.23 (br, 4H), 3.15-3.05 (m, 2H), 2.68 (s, 3H), 2.28-1.91 (m, 2H),1.51-1.28 (m, 15H).

Preparation Example 22 Preparation of Dimer D6

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D6): Into a 500-mL round-bottom flask, was placed dichloromethane (400mL),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (20 g, 75.96 mmol, 1.00 equiv), benzyl(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate (25.8g, 76.24 mmol, 1.00 equiv). This was followed by the addition of HOBT(12 g, 88.81 mmol, 1.15 equiv), DCC (18 g, 87.24 mmol, 1.15 equiv) and4-dimethylaminopyridine (10.7 g, 87.58 mmol, 1.15 equiv) respectively inportions with stirring at 0° C. The resulting solution was stirred for 4h at room temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10-1:5). This resulted in80 g (90%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 584 (M+H); ¹HNMR (300 MHz, CDCl₃, ppm):δ 7.37-7.16 (m, 7H), 7.14 (d, J=8.4 Hz, 2H), 6.12 (s, 1H), 5.28-5.25 (m,1H), 5.15-5.13 (m, 2H), 5.12-4.81 (m, 1H), 4.35-4.33 (m, 2H), 3.95 (t,J=8.7 Hz, 2H), 3.18-3.14 (m, 2H), 2.68 (d, J=12.9 Hz, 3H), 2.53-2.49 (m,2H), 2.22-2.10 (m, 1H), 2.06-1.85 (m, 1H), 1.48 (d, J=16.8 Hz, 9H), 1.39(s, 3H), 1.32 (s, 3H).

Preparation Example 23 Preparation of Dimer D7

(2R)-1-(benzyloxy)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D7): Into a 100-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (700 mg, 2.66 mmol, 1.00 equiv), DCM (30 mL), benzyl(2S)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-2-hydroxypropanoate (513 mg, 1.43mmol, 1.00 equiv). This was followed by the addition of HOBT (262 mg,1.94 mmol, 1.10 equiv), DCC (442 mg, 2.14 mmol, 1.10 equiv) and4-dimethylaminopyridine (290 mg, 2.37 mmol, 1.10 equiv) respectively inportions with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 850 mg (53%) of(2R)-1-(benzyloxy)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 604 (M+H).

Preparation Example 24 Preparation of Dimer D8

(2R)-1-(benzyloxy)-3-(4-tert-butylphenyl)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D8): Into a 1000-mL 3-necked round-bottom flask, was placed a solutionof(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (25 g, 94.95 mmol, 1.00 equiv) in dichloromethane (1000 mL), benzyl(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate (30 g, 96.03 mmol, 1.00equiv), DCC (40 g, 193.86 mmol, 2.00 equiv), HOBT (26 g, 192.42 mmol,2.00 equiv), 4-dimethylaminopyridine (23.5 g, 192.35 mmol, 2.00 equiv).The resulting solution was stirred for 2 h at room temperature in anice/salt bath. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:50˜1:10). This resulted in 50 g (94%) of(2R)-1-(benzyloxy)-3-(4-tert-butylphenyl)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 558 (M+H); ¹HNMR (300 MHz, CDCl₃, ppm):δ 7.35-7.27 (m, 7H), 7.12-7.09 (m, 2H), 5.27-4.62 (m, 4H), 3.15-3.09 (m,2H), 2.69-2.61 (m, 3H), 2.20-1.82 (m, 2H), 1.61-1.31 (m, 24H).

Preparation Example 25 Preparation of Dimer D9

2-(Benzyloxy)-2-oxoethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D9): Into a 100-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid (1.5 g, 6.17 mmol, 1.00 equiv), benzyl 2-hydroxyacetate (1.02 g,6.14 mmol, 1.00 equiv) in dichloromethane (30 mL). This was followed bythe addition of DCC (1.52 g, 7.37 mmol, 1.20 equiv),4-dimethylaminopyridine (900 mg, 7.37 mmol, 1.20 equiv) and HOBt (1.0 g,7.40 mmol, 1.20 equiv) respectively in portions with stirring at 0° C.The resulting solution was stirred for 12 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (3:1). Thisresulted in 2 g (83%) of 2-(benzyloxy)-2-oxoethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate asyellow oil. MS (ES, m/z): 392 (M+H); ¹HNMR (300 MHz,CDCl₃, ppm): δ7.42-7.32 (m, 5H), 5.19 (s, 2H), 4.96-4.91 (m, 0.5H), 4.71-4.65 (m, 2H),4.65-4.63 (m, 0.5H), 2.87 (d, J=14.1 Hz, 3H), 1.90-1.62 (m, 2H), 1.47(d, J=6.0 Hz, 9H), 0.78-0.67 (m, 1H), 0.49-0.42 (m, 2H), 0.13-0.09 (m,2H).

Preparation Example 26 Preparation of Monomer D10

(S)(R)-1-(benzyloxy)-1-oxopropan-2-yl)2-(tert-butoxycarbonyl(methyl)amino)-3-cyclopropylpropanoate (D10): Intoa 500-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid (4 g, 16.44 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (3g, 16.65 mmol, 1.00 equiv), PPh₃ (5.2 g, 19.83 mmol, 1.20 equiv),tetrahydrofuran (150 mL). This was followed by the addition of asolution of DEAD (3.5 g, 20.10 mmol, 1.20 equiv) in tetrahydrofuran (30mL) dropwise with stirring at 0° C. The resulting solution was stirredfor overnight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:20). Thisresulted in 7 g (crude) of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate ascolorless oil. MS (ES, m/z): 406 (M+H).

Preparation Example 27 Preparation of Monomer D11

Benzyl(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-2-cyclopropylacetyl]oxy]propanoate(D11): Into a 250-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-2-cyclopropylacetic acid(3.4 g, 14.83 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (2.7 g,14.98 mmol, 1.00 equiv), tetrahydrofuran (100 mL), PPh₃ (3.1 g, 11.82mmol, 1.20 equiv). This was followed by the addition of DEAD (4.7 g,26.99 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred overnight at room temperature. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:15). Thisresulted in 4.2 g (72%) of benzyl(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-2-cyclopropylacetyl]oxy]propanoateas yellow oil. MS (ES, m/z): 392 (M+H); ¹HNMR (300 MHz, CDCl₃, ppm): δ7.41-7.34 (m, 5H), 5.24-5.15 (m, 3H), 4.08-3.66 (m, 1H), 2.97 (br, 3H),1.53 (d, J=6.9 Hz, 3H), 1.46 (s, 9H), 1.25-1.14 (m, 1H), 0.78-0.72 (m,1H), 0.60-0.55 (m, 2H), 0.39-0.34 (m, 1H).

Preparation Example 28 Preparation of Monomer D12

(2R)-1-(benzyloxy)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D12): Into a 100-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed tetrahydrofuran (25mL), benzyl(2S)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-2-hydroxypropanoate (710mg, 2.00 mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (527 mg, 2.00 mmol, 1.00 equiv), PPh₃ (790 mg, 3.01 mmol, 1.50equiv). This was followed by the addition of DEAD (517 mg, 2.97 mmol,1.50 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 2 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by thin layerchromatography developed with ethyl acetate/PE (1/5). This resulted in710 mg (59%) of(2R)-1-(benzyloxy)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 600 (M+H).

Preparation Example 29 Preparation of Monomer D13

(2R)-1-(benzyloxy)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D13): Into a 100-mL round-bottom flask, was placed dichloromethane (50mL), benzyl(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate (2g, 5.37 mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (1.42 g, 5.39 mmol, 1.10 equiv). This was followed by the additionof HOBT (870 mg, 6.44 mmol, 1.20 equiv), in portions. To this was addedDCC (1.33 g, 6.45 mmol, 1.20 equiv), in portions. To the mixture wasadded 4-dimethylaminopyridine (780 mg, 6.38 mmol, 1.20 equiv), inportions. The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:20-1:15). This resulted in 3.2 g (96%) of(2R)-1-(benzyloxy)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 618 (M+H); ¹HNMR(300 MHz,CDCl3, ppm): δ7.36-7.34 (m, 5H), 7.26-7.25(m,2H), 7.14-7.11(m,2H), 5.89(br, 1H),5.29-5.23(m,1H), 5.18-5.06(m,2H), 4.89-4.78(m,1H), 3.17-3.10(m,2H),2.77-2.65(m,7H), 2.23-1.97(m,2H), 1.59-1.15 (m,17H).

Preparation Example 30 Preparation of Monomer D14

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D14): Into a 250-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (3.1 g, 11.77 mmol, 1.00 equiv), benzyl(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate (4 g, 11.75mmol, 1.00 equiv), dichloromethane (120 mL). This was followed by theaddition of DCC (2.7 g, 13.09 mmol, 1.10 equiv), 4-dimethylaminopyridine(1.6 g, 13.10 mmol, 1.10 equiv) and HOBt (1.7 g, 12.58 mmol, 1.10 equiv)respectively in portions with stirring at 0° C. The resulting solutionwas stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 3.5 g(51%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas yellow oil. MS (ES, m/z): 586 (M+H); ¹HNMR (300 MHz, CDCl₃, ppm): δ7.39-7.37 (m, 4H), 7.28-7.26 (m, 1H), 7.19-7.08 (m, 4H), 5.30-5.27 (m,1H), 5.22-5.10 (m, 2H), 5.05-4.82 (m, 1H), 3.19-3.16 (m, 2H), 2.66 (d,J=22.5 Hz, 3H), 2.28-2.16 (m, 1H), 2.07-1.92 (m, 1H), 1.51-1.33 (m,15H).

Preparation Example 31 Preparation of Monomer D15

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D15): Into a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed benzyl(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoate(700 mg, 1.96 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (776 mg, 2.95 mmol, 1.50 equiv), PPh₃ (1.03 g, 3.93 mmol, 2.00equiv), tetrahydrofuran (50 mL). This was followed by the addition ofDEAD (684 mg, 3.93 mmol, 2.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1/4). Thisresulted in 950 mg (80%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas light yellow oil. MS (ES, m/z): 602 (M+H); ¹HNMR (300 MHz, CD₃OD,ppm): δ 7.36-7.28 (m, 5H), 7.14-7.12 (m, 1H), 6.97-6.93 (m, 2H), 6.03(br, 1H), 5.33-5.31 (m, 1H), 5.17-5.12 (m, 2H), 4.93-4.90 (m, 0.5H),4.73-4.56 (m, 0.5H), 4.34-4.23 (m, 2H), 3.88-3.83 (m, 2H), 3.15-3.12 (m,2H), 2.75-2.71 (m, 3H), 2.50 (br, 2H), 2.31-1.97 (m, 2H), 1.47-1.23 (m,15H).

Preparation Example 32 Preparation of Monomer D16

Benzyl(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]propanoate(D16): Into a 100-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropane-1-carboxylic acid(2 g, 9.29 mmol, 1.00 equiv), PPh₃ (7.3 g, 27.83 mmol, 3.00 equiv),tetrahydrofuran (35 mL), benzyl (2S)-2-hydroxypropanoate (2.02 g, 11.21mmol, 1.20 equiv). This was followed by the addition of DEAD (4.86 g,27.91 mmol, 3.00 equiv) dropwise with stirred at 0° C. in 10 min. Theresulting solution was stirred for 2 h at room temperature. The reactionwas then quenched by the addition of 100 mL of water. The resultingsolution was extracted with 3×40 mL of ethyl acetate and the organiclayers combined and washed with 1×30 mL of brine. The organic layerswere collected and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:3). This resulted in 2.8 g (80%) ofbenzyl (2R)-2-[(1-[[(tertbutoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]propanoate asorange oil. MS (ES, m/z): 378 (M+H).

Preparation Examples 33 to 40 below are non-limiting illustrations ofthe methods used to prepare the compounds of the invention. The skilledperson will understand that these methods may be adapted to prepareother compounds of the invention.

Preparation Example 33 Preparation of Compound 6-7A in Table 6, whereinR^(a), R^(b), R′, R″, R′″ and R″″ are Each Methyl

Compound 6-7A was prepared according to Schemes 2 and 3 shown below.

Experimental Details

(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-3-[4-(morpholin-4-yl)phenyl]propanoicacid (DC1): Into a 250-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(2.5 g, 4.41 mmol, 1.00 equiv), methanol (100 mL), Palladium carbon (500mg). To the above mixture was introduced hydrogen. The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 2 g (95%) of(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-3-[4-(morpholin-4-yl)phenyl]propanoicacid as a white solid. MS (ES, m/z): 477 (M+H).

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-4-methyl-2-(methylamino)pentanoate (DA2): Into a 100-mL 3-neckedround-bottom flask, was placed (2R)-1- (benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate (3.50g, 8.35 mmol, 1.00 equiv), dichloromethane (20 mL), HCl (gas)/dioxane(50 mL). The resulting solution was stirred for 1.0 h at roomtemperature. The resulting mixture was concentrated under vacuum. The pHvalue of the solution was adjusted to 8 with sodium bicarbonate (Sat.).The resulting solution was extracted with 3×100 mL of dichloromethaneand the organic layers combined and washed with 3×100 mL of brine. Theorganic phase was collected and dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 2.42 g (94%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-4-methyl-2-(methylamino)pentanoate as colorless oil. MS (ES, m/z):308 (M+H).

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoate(TP6-7): Into a 250-mL 3-necked round-bottom flask, was placed(2R)-1-(benzyloxy)-1-oxopropan-2-yl (2S)-4-methyl-2-(methylamino)pentanoate (1.35 g, 4.39 mmol, 1.00 equiv),(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-3-[4-(morpholin-4-yl)phenyl]propanoicacid (2 g, 4.20 mmol, 1.00 equiv), dichloromethane (100 mL). This wasfollowed by the addition of BOP-Cl (2.14 g, 8.41 mmol, 2.00 equiv) inportions at 0° C. To this was added DIEA (1.08 g, 8.36 mmol, 2.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 2 g (59%) of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoateas yellow oil. MS (ES, m/z): 766 (M+H).

(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoyl]oxy]propanoicacid (TC6-7): Into a 250-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoate(1 g, 1.31 mmol, 1.00 equiv), methanol (100 mL), Palladium carbon (300mg). To the above mixture was introduced hydrogen. The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 800 mg (91%) of(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoyl]oxy]propanoicacid as a white solid. MS (ES, m/z): 676 (M+H).

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoate(TA6-7): Into a 250-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoate(1 g, 1.31 mmol, 1.00 equiv), HCl (gas)/dioxane (50 mL). The resultingsolution was stirred for 1 h at room temperature. The pH value of thesolution was adjusted to 8 with sodium bicarbonate aq (Sat.). Theresulting solution was extracted with 3×100 mL of dichloromethane andthe organic layers combined and washed with 3×100 mL of brine. Theorganic phase was collected and dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 820 mg (94%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoateas yellow oil. MS (ES, m/z): 666 (M+H).

[(1R)-2-[[(1S)-2-[(1R)-2-[[(1S)-1-[(1R)-2-benzyloxy-1-methyl-2-oxo-ethoxy]carbonyl-3-methyl-butyl]-methyl-amino]-1-[(4-morpholinophenyl)methyl]-2-oxo-ethoxy]-1-(cyclopropylmethyl)-2-oxo-ethyl]-methyl-amino]-1-methyl-2-oxo-ethyl](2S)-2-[[(2R)-2-[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-cyclopropyl-propanoyl]oxy-3-(4-morpholinophenyl)propanoyl]-methyl-amino]-4-methyl-pentanoate(OP6-7): Into a 250-mL 3-necked round-bottom flask, was placed(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoyl]oxy]propanoicacid (800 mg, 1.18 mmol, 1.00 equiv),(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoate(788 mg, 1.18 mmol, 1.00 equiv), dichloromethane (120 mL). This wasfollowed by the addition of BOP-Cl (602 mg, 2.00 equiv) in portions at0° C. To this was added DIEA (304 mg, 2.35 mmol, 2.00 equiv) dropwisewith stirring at 0° C. The resulting solution was stirred overnight atroom temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1). This resulted in 850 mg(54%) of OP6-7 as a yellow solid. MS (ES, m/z): 1324 (M+H).

(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]ethyl(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoate(OA6-7): Into a 100-mL round-bottom flask, was placed OP6-7 (850 mg,0.64 mmol, 1.00 equiv), HCl (gas)/dioxane (20 mL). The resultingsolution was stirred for 1 h at room temperature. The pH value of thesolution was adjusted to 8 with sodium bicarbonate (aq.). The resultingsolution was extracted with 3×60 mL of dichloromethane and the organiclayers combined and washed with 3×100 mL of brine. The organic phase wascollected and dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 800 mg (crude) of(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]ethyl(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoate(OA6-7) as a yellow solid. MS (ES, m/z): 1224 (M+H).

(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoyl]oxy]-N-methylpropanamido]propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoyl]oxy]propanoicacid (OAC6-7): Into a 100-mL round-bottom flask, was placed OA6-7 (800mg, 0.65 mmol, 1.00 equiv), methanol (50 mL), Palladium carbon (100 mg).To the above mixture was introduced hydrogen. The resulting solution wasstirred for 1 h at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. This resulted in 720 mg (97%) of(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoyl]oxy]-N-methylpropanamido]propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-4-methylpentanoyl]oxy]propanoicacid (OAC6-7) as a white solid. MS (ES, m/z): 1134 (M+H).

(3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(cyclopropylmethyl)-4,6,10,16,18,22-hexamethyl-9,21-bis(2-methylpropyl)-12,24-bis([[4-(morpholin-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(6-7A): Into a 250-mL 3-necked round-bottom flask, was placed OAC6-7(720 mg, 0.64 mmol, 1.00 equiv), dichloromethane (200 mL). This wasfollowed by the addition of BOP-Cl (324 mg, 1.27 mmol, 2.00 equiv) inportions at 0° C. To this was added DIEA (164 mg, 1.27 mmol, 2.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The crude product was purifiedby Prep-HPLC with the following conditions (waters-2767): Column,SunFire Prep C18, 5 μm, 19*150 mm; mobile phase, Water and CH₃CN (70%CH₃CN up to 80% in 8 min); Detector, UV 220 nm. This resulted in 53.6 mg(8%) of(3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(cyclopropylmethyl)-4,6,10,16,18,22-hexamethyl-9,21-bis(2-methylpropyl)-12,24-bis([[4-(morpholin-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(6-7A) as a white solid. ¹H-NMR (CD₃OD, 300 MHz) δ: 7.22-7.15 (m, 4H),6.94-6.85 (m, 4H), 5.73-5.62 (m, 2H), 5.55-5.15 (m, 5H), 4.82-4.72 (m,1H), 3.85-3.75 (m, 8H), 3.15-2.98 (m, 18H), 2.98-2.86 (m, 6H), 2.22-1.35(m, 12H), 1.01-0.98 (m, 3H), 0.94-0.69 (m, 14H), 0.69-0.05 (m, 9H); MS(ES, m/z): 1116.0 (M+H); [a]=−91.66°, T=27.2° C., C=0.90 g/100 mL inMeOH.

Preparation Example 34 Preparation of Compound 9-7A in Table 9, whereinR^(a), R^(b), R′, R″, R′″ and R″″ are Each Methyl

Compound 9-7A was prepared in a similar way to compound 6-7A accordingto Schemes 4 and 5 shown below.

Experimental Details

(2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D3): Into a 100-mL round-bottom flask, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid (700 mg, 2.88 mmol, 1.00 equiv), dichloromethane (20 mL), benzyl(2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate (1 g, 2.92mmol, 1.00 equiv). This was followed by the addition of DCC (660 mg,3.20 mmol, 1.10 equiv), 4-dimethylaminopyridine (400 mg, 3.27 mmol, 1.10equiv) and HOBT (440 mg, 3.26 mmol, 1.10 equiv) in portions at 0° C. Theresulting solution was stirred overnight at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:3). This resulted in 1 g (61%) of(2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D3) as a white solid. MS (ESI, m/z): 568 [M+H]⁺.

(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoicacid (DC3): Into a 250-mL round-bottom flask, was placed a solution of(2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D3, 1.1 g, 1.94 mmol, 1.00 equiv), methanol (15 mL) and Palladiumcarbon (100 mg). To the above mixture was introduced hydrogen. Theresulting solution was stirred for 1 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted in 1 g (crude) of(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoicacid as a white solid. MS (ESI, m/z): 478 [M+H]⁺.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[6-(morpholin-4-yl)pyridin-3-yl]propanamido]-4-methylpentanoate(TP9-7): Into a 100-mL 3-necked round-bottom flask, was placed asolution of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-4-methyl-2-(methylamino)pentanoate (1 g, 3.25 mmol, 1.00 equiv),dichloromethane (30 mL) and(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoicacid (650 mg, 1.36 mmol, 1.00 equiv). This was followed by the additionof BOP-Cl (1.1 g, 2.00 equiv) in portions at 0° C. To this was addedDIEA (540 mg, 4.18 mmol, 2.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred overnight at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2). This resulted in 1.3 g (52%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[6-(morpholin-4-yl)pyridin-3-yl]propanamido]-4-methylpentanoateas a white solid. MS (ESI, m/z): 767 [M+H]⁺.

(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[6-(morpholin-4-yl)pyridin-3-yl]propanamido]-4-methylpentanoyl]oxy]propanoicacid (TC9-7): Into a 100-mL round-bottom flask, was placed a solution of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[6-(morpholin-4-yl)pyridin-3-yl]propanamido]-4-methylpentanoate(650 mg, 0.85 mmol, 1.00 equiv), methanol (15 mL) and Palladium carbon(100 mg). To the above mixture was introduced hydrogen. The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 560 mg (98%) of(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[6-(morpholin-4-yl)pyridin-3-yl]propanamido]-4-methylpentanoyl]oxy]propanoicacid as a white solid. MS (ESI, m/z): 677 [M+H]⁺.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[6-(morpholin-4-yl)pyridin-3-yl]propanamido]-4-methylpentanoate(TA9-7): Into a 100-mL round-bottom flask, was placed a solution of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[6-(morpholin-4-yl)pyridin-3-yl]propanamido]-4-methylpentanoate(650 mg, 0.85 mmol, 1.00 equiv), dichloromethane (10 mL). To this wasadded trifluoroacetic acid (1 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 1 h at room temperature. The pH valueof the solution was adjusted to 9 with sodium bicarbonate (aq.). Theresulting solution was extracted with 3×20 mL of dichloromethane and theorganic layers combined. The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 550 mg(97%) of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[6-(morpholin-4-yl)pyridin-3-yl]propanamido]-4-methylpentanoateas a light yellow semi-solid. MS (ESI, m/z): 667 [M+H]⁺.

OP9-7: Into a 250-mL 3-necked round-bottom flask, was placed a solutionof TC9-7 (560 mg, 0.83 mmol, 1.00 equiv), dichloromethane (50 mL) andTA9-7 (550 mg, 0.82 mmol, 1.00 equiv). This was followed by the additionof BOP-Cl (421 mg, 2.00 equiv) in portions at 0° C. To this was addedDIEA (210 mg, 1.62 mmol, 2.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred overnight at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 600 mg (55%) of 9-7-6 ascolorless oil. MS (ESI, m/z): 1326 [M+H]⁺.

OA9-7: Into a 100-mL 3-necked round-bottom flask, was placed a solutionof OP9-7 (600 mg, 0.45 mmol, 1.00 equiv), dioxane (20 mL). To the abovehydrogen chloride (gas) was introduced in. The resulting solution wasstirred for 1 h at room temperature. The resulting solution was stirredfor 1 h at room temperature. The pH value of the solution was adjustedto 9 with sodium bicarbonate (aq.). The resulting solution was extractedwith 3×20 mL of dichloromethane and the organic layers combined. Theorganic phase was dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 510 mg (crude) of OA9-7 as a yellowsemi-solid. MS (ESI, m/z): 1226 [M+H]⁺.

OAC9-7: Into a 100-mL round-bottom flask, was placed a solution of OA9-7(510 mg, 0.42 mmol, 1.00 equiv), methanol (10 mL) and Palladium carbon(50 mg). To the above mixture was introduced hydrogen. The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 480 mg (crude) of OAC9-7 as a white solid. MS (ESI, m/z): 1136[M+H]⁺.

(3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(cyclopropylmethyl)-4,6,10,16,18,22-hexamethyl-9,21-bis(2-methylpropyl)-12,24-bis([[6-(morpholin-4-yl)pyridin-3-yl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(9-7A): Into a 250-mL 3-necked round-bottom flask, was placed a solutionof OAC9-7 (480 mg, 0.042 mmol, 1.00 equiv) and DCM (100 mL). This wasfollowed by the addition of BOP-Cl (216 mg, 0.85 mmol, 2.00 equiv) inportions at 0° C. To this was added DIEA (110 mg, 0.85 mmol, 2.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The crude product was purifiedby Prep-HPLC with the following conditions (waters-2767): Column,SunFire Prep C18, 5 um, 19*150 mm; mobile phase, 0.05% Trifluoroaceticacid in water and CH₃CN (70% CH₃CN up to 80% in 8 min); Detector, UV 254nm. This resulted in 57.2 mg (12%) of (3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(cyclopropylmethyl)-4,6,10,16,18,22-hexamethyl-9,21-bis(2-methylpropyl)-12,24-bis([[6-(morpholin-4-yl)pyridin-3-yl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(9-7) as a white solid. ¹H NMR (CD₃OD, 300 MHz) δ: 8.1-7.9 (m, 2H),7.60-7.50 (m, 2H), 6.85-6.65 (m, 2H), 5.90-5.10 (m, 7H), 4.80-4.70 (m,1H), 3.85-3.65 (m, 8H), 3.55-3.40 (m, 8H), 3.20-2.80 (m, 16H), 2.25-1.30(m, 12H), 1.10-0.70 (m, 17H), 0.70-0.35 (m, 5H), 0.30-0.01 (m, 4H); MS(ESI, m/z): 1118 [M+H]⁺; [α]=−77.34°, T=27.2° C., C=1.00 g/100 mL, MeOH.

Preparation Example 35 Synthesis of Compound 6-34A in Table 6, WhereinR^(a), R^(b), R′, R″, R′″ and R″″ are Each Methyl

Compound 6-30A was prepared in a similar way to compound 6-7A accordingto Schemes 6 and 7 shown below.

Experimental Details

(R)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoyloxy)-3-(4-morpholinophenyl)propanoicacid (DC5): Into a 250-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D5, 3.5 g, 5.97 mmol, 1.00 equiv), methanol (100 mL), Palladium carbon(1 g). To the above mixture was introduced hydrogen. The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 3 g (crude) of(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(morpholin-4-yl)phenyl]propanoicacid as a white solid. MS (ES, m/z): 497 (M+H).

(S)-((R)-1-(((S)-((R)-1-(benzyloxy)-1-oxopropan-2-yloxy)-3-cyclopropyl-1-oxopropan-2-yl)(methyl)amino)-3-(4-morpholinophenyl)-1-oxopropan-2-yl)2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoate(TP6-34): Into a 250-mL 3-necked round-bottom flask, was placed(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-3-cyclopropyl-2-(methylamino)propanoate (DA2, 1.8 g, 5.89 mmol,1.00 equiv),(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(morpholin-4-yl)phenyl]propanoicacid (DCS, 3 g, 6.04 mmol, 1.00 equiv), dichloromethane (120 mL). Thiswas followed by the addition of BOP-Cl (3.1 g, 12.18 mmol, 2.00 equiv)in portions at 0° C. To this was added DIEA (1.6 g, 12.38 mmol, 2.00equiv) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:6). Thisresulted in 3 g (65%) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas yellow oil. MS (ES, m/z): 784 (M+H).

(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]propanoicacid (TC6-34): Into a 250-mL round-bottom flask, was placed(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(TP6-34, 1.5 g, 1.91 mmol, 1.00 equiv), methanol (100 mL), Palladiumcarbon (500 mg). To the above mixture was introduced hydrogen. Theresulting solution was stirred for 1 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted in 1.1 g (83%) of(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]propanoicacid as a white solid. MS (ES, m/z): 694 (M+H).

(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (TA6-34): Into a 250-mL3-necked round-bottom flask, was placed(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(TP6-34, 1.5 g, 1.91 mmol, 1.00 equiv), dichloromethane (100 mL). To theabove HCl (gas) was introduced in. The resulting solution was stirredfor 1 h at room temperature. The pH value of the solution was adjustedto 8 with sodium bicarbonate (aq). The resulting solution was extractedwith 3×80 mL of dichloromethane and the organic layers combined andwashed with 3×100 mL of brine. The organic phase was collected and driedover anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 1.3 g (99%) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate as yellow oil. MS (ES,m/z): 684 (M+H).

[(1R)-2-[[(1S)-2-[(1R)-2-benzyloxy-1-methyl-2-oxo-ethoxy]-1-(cyclopropylmethyl)-2-oxo-ethyl]-methyl-amino]-1-[(4-morpholinophenyl)methyl]-2-oxo-ethyl](2S)-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-(4-morpholinophenyl)propanoyl]-methyl-amino]-3-cyclopropyl-propanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoate(OP6-34): Into a 250-mL 3-necked round-bottom flask, was placed(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]propanoicacid (TC6-34, 1.1 g, 1.59 mmol, 1.00 equiv),(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (TA6-34, 1.1 g, 1.61mmol, 1.00 equiv), dichloromethane (120 mL). This was followed by theaddition of BOP-Cl (808 mg, 3.17 mmol, 2.00 equiv) in portions at 0° C.To this was added DIEA (409 mg, 3.16 mmol, 2.00 equiv) dropwise withstirring at 0° C. The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The filtrate was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:1). This resulted in 1.5 g (70%) ofOP6-34 as a yellow solid. MS (ES, m/z): 1360 (Ms+H).

(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethoxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (OA6-34): Into a 250-mL3-necked round-bottom flask, was placed OP6-34 (1.5 g, 1.10 mmol, 1.00equiv), dichloromethane (100 mL). To the above HCl (gas) was introducedin. The resulting solution was stirred for 1 h at room temperature. ThepH value of the solution was adjusted to 8 with sodium bicarbonate (aq).The resulting solution was extracted with 3×100 mL of dichloromethaneand the organic layers combined and washed with 3×100 mL of brine. Theorganic phase was collected and dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 1.1 g (79%) of(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethoxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate as a yellow solid. MS(ES, m/z): 1260 (M+H).

(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]propanoicacid (OAC6-34): Into a 250-mL round-bottom flask, was placed1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethoxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (OA6-34, 1.1 g, 0.87mmol, 1.00 equiv), methanol (100 mL), Palladium carbon (300 mg). To theabove mixture was introduced hydrogen. The resulting solution wasstirred for 1 h at room temperature. The solids were filtered out. Thefiltrate mixture was concentrated under vacuum. This resulted in 1 g(98%) of(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]propanoicacid as a white solid. MS (ES, m/z): 1170 (M+H).

(3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(cyclopropylmethyl)-9,21-bis(2-fluoro-2-methylpropyl)-4,10,12,16,22,24-hexamethyl-6,18-bis([[4-(morpholin-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(6-34A): Into a 250-mL 3-necked round-bottom flask, was placed(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]propanoicacid (OAC6-34, 300 mg, 0.26 mmol, 1.00 equiv), dichloromethane (150 mL).This was followed by the addition of BOP-Cl (131 mg, 0.51 mmol, 2.00equiv) in portions at 0° C. To this was added DIEA (66 mg, 0.51 mmol,2.00 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The crude product was purifiedby Prep-HPLC with the following conditions (waters-2767): Column,SunFire Prep C18, 5 um, 19*150 mm; mobile phase, Water and CH₃CN (70%CH₃CN up to 80% in 8 min); Detector, UV 220 nm. This resulted in 72.3 mg(24%) of(3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(cyclopropylmethyl)-9,21-bis(2-fluoro-2-methylpropyl)-4,10,12,16,22,24-hexamethyl-6,18-bis([[4-(morpholin-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octoneas a white solid. MS (ES, m/z): 1152 (M+H); ¹H NMR: (300 MHz, CD₃OD,ppm): δ 7.19-7.12 (m, 4H), 6.98-6.81 (m, 4H), 5.88-5.55 (m, 2H),5.55-5.16 (m, 5H), 5.01-4.88 (m, 1H), 3.92-3.78 (m, 8H), 3.19-2.82 (m,24H), 2.35-2.00 (m, 4H), 1.92-1.55 (m, 3H), 1.55-1.20 (m, 18H),1.02-0.91 (m, 1H), 0.55-0.11 (m, 10H); MS (ESI, m/z): 1152 [M+H]⁺;[a]=−71.7°, T=27.2° C., C=0.75 g/100 mL in MeOH.

Preparation Example 36 Synthesis of Compound 6-1A in Table 6, WhereinR′, R″, R′″ and R″″ are Each Methyl

Compound 6-1A was prepared in a similar way to compound 6-7A accordingto Schemes 8 and 9 shown below.

Experimental Details

(S)-((R)-1-(benzyloxy)-1-oxopropan-2-yl)2-(tert-butoxycarbonyl(methyl)amino)-3-cyclopropylpropanoate (D10): Intoa 500-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid (4 g, 16.44 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (3g, 16.65 mmol, 1.00 equiv), PPh₃ (5.2 g, 19.83 mmol, 1.20 equiv),tetrahydrofuran (150 mL). This was followed by the addition of asolution of DEAD (3.5 g, 20.10 mmol, 1.20 equiv) in tetrahydrofuran (30mL) dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:20). Thisresulted in 7 g (crude) of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate ascolorless oil. MS (ESI, m/z): 406 [M+H]⁺.

(S)-((R)-1-(benzyloxy)-1-oxopropan-2-yl)3-cyclopropyl-2-(methylamino)propanoate (DA10): Into a 500-mLround-bottom flask, was placed (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D10, 7 g, 17.26 mmol, 1.00 equiv), dichloromethane (200 mL). To theabove HCl (gas) was introduced. The resulting solution was stirred for 1h at room temperature. The pH value of the solution was adjusted to 8with sodium bicarbonate (aq). The resulting solution was extracted with3×200 mL of dichloromethane and the organic layers combined. The organiclayers were washed with 3×200 mL of brine. The organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 4 g (76%) of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-3-cyclopropyl-2-(methylamino)propanoate as yellow oil. MS (ESI,m/z): 306 [M+H]⁺.

(S)-((R)-1-(((S)-1-((R)-1-(benzyloxy)-1-oxopropan-2-yloxy)-3-cyclopropyl-1-oxopropan-2-yl)(methyl)amino)-3-(4-morpholinophenyl)-1-oxopropan-2-yl)2-(tert-butoxycarbonyl(methyl)amino)-3-cyclopropylpropanoate (TP6-1):Into a 250-mL 3-necked round-bottom flask, was placed(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-3-cyclopropyl-2-(methylamino)propanoate (DA10, 900 mg, 2.95 mmol,1.00 equiv),(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-3-[4-(morpholin-4-yl)phenyl]propanoicacid (DC1, 1.3 g, 2.73 mmol, 1.00 equiv), dichloromethane (80 mL). Thiswas followed by the addition of BOP-Cl (1.5 g, 5.89 mmol, 2.00 equiv) inportions at 0° C. To this was added DIEA (770 mg, 5.96 mmol, 2.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:4). Thisresulted in 1.7 g (76%) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate asyellow oil. MS (ESI, m/z): 764 [M+H]⁺.

(S)—((R)-1-(benzyloxy)-1-oxopropan-2-yl)3-cyclopropyl-2-((R)-2-((S)-3-cyclopropyl-2-(methylamino)propanoyloxy)-N-methyl-3-(4-morphohnophenyl)propanamido)propanoate(TA6-1): Into a 100-mL round-bottom flask, was placed(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(TP6-1) (800 mg, 1.05 mmol, 1.00 equiv), dichloromethane (60 mL). To theabove HCl (gas) was introduced in. The resulting solution was stirredfor 1 h at room temperature. The pH value of the solution was adjustedto 8 with sodium bicarbonate (aq). The resulting solution was extractedwith 3×50 mL of dichloromethane and the organic layers combined. Theorganic layers were washed with 3×60 mL of brine. The organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.This resulted in 650 mg (94%) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-3-cyclopropyl-2-(methylamino)propanoate as yellow oil. MS (ESI,m/z): 664 [M+H]⁺.

(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]propanoicacid (TC6-1): Into a 250-mL round-bottom flask, was placed(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(TP6-1, 800 mg, 1.05 mmol, 1.00 equiv), Palladium carbon (100 mg),methanol (80 mL). To the above hydrogen was introduced. The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Thisresulted in 620 mg (88%) of(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]propanoicacid as a white solid. MS (ESI, m/z): 674 [M+H]⁺.

Compound OP6-1: Into a 250-mL 3-necked round-bottom flask, was placed asolution of TC6-1 (620 mg, 0.92 mmol, 1.00 equiv), dichloromethane (100mL), TA6-1 (611 mg, 0.92 mmol, 1.00 equiv). This was followed by theaddition of BOP-Cl (469 mg, 2.00 equiv) in portions at 0° C. To this wasadded DIEA (237 mg, 1.83 mmol, 2.00 equiv) dropwise with stirring at 0°C. The resulting solution was stirred overnight at room temperature. Thesolids were filtered out. The filtrate was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1/1). This resulted in 450 mg (37%) of OP6-1 asyellow oil. MS (ESI, m/z): 1320 [M+H]⁺.

(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-3-cyclopropyl-2-(methylamino)propanoate (OA6-1): Into a 100-mLround-bottom flask, was placed OP6-1 (450 mg, 0.34 mmol, 1.00 equiv),dichloromethane (50 mL). To the above HCl (g) was introduced in. Theresulting solution was stirred for 1 h at room temperature. The pH valueof the solution was adjusted to 8 with sodium bicarbonate (aq). Theresulting solution was extracted with 3×50 mL of dichloromethane and theorganic layers combined. The organic layer was washed with 3×70 mL ofbrine. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 300 mg (72%) of(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-3-cyclopropyl-2-(methylamino)propanoate as yellow oil. MS (ESI,m/z): 1220 [M+H]⁺.

(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]-N-methylpropanamido]propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]propanoicacid (OAC6-1): Into a 100-mL round-bottom flask, was placed(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(morpholin-4-yl)phenyl]ethyl(2S)-3-cyclopropyl-2-(methylamino)propanoate (OAC6-1) (300 mg, 0.25mmol, 1.00 equiv), methanol (50 mL), Palladium carbon (100 mg). To theabove mixture was introduced hydrogen. The resulting solution wasstirred for 1 h at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. This resulted in 200 mg (72%) of(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]-N-methylpropanamido]propanoyl]oxy]-N-methyl-3-[4-(morpholin-4-yl)phenyl]propanamido]propanoyl]oxy]propanoicacid as a white solid. MS (ESI, m/z): 1130 [M+H]⁺.

(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetrakis(cyclopropylmethyl)-4,10,12,16,22,24-hexamethyl-6,18-bis([[4-(morpholin-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(6-1A): Into a 250-mL 3-necked round-bottom flask, was placed OAC6-1(200 mg, 0.18 mmol, 1.00 equiv), dichloromethane (120 mL). This wasfollowed by the addition of BOP-Cl (90 mg, 0.35 mmol, 2.00 equiv) inportions at 0° C. To this was added DIEA (46 mg, 0.36 mmol, 2.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The crude product was purifiedby Prep-HPLC with the following conditions (waters-2767): Column,SunFire Prep C18, 5 um, 19*150 mm; mobile phase, Water and CH₃CN (70%CH₃CN up to 80% in 8 min); Detector, UV 254 nm. This resulted in 24.7 mg(13%) of(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetrakis(cyclopropylmethyl)-4,10,12,16,22,24-hexamethyl-6,18-bis([[4-(morpholin-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octoneas a white solid. ¹H NMR (CD₃OD, 300 MHz) δ: 7.31-7.08 (m, 4H),6.98-6.81 (m, 4H), 5.08-5.02 (m, 7H), 4.82-4.68 (m, 1H), 3.92-3.76 (m,8H), 3.25-2.82 (m, 24H), 2.51-1.18 (m, 13H), 1.08-0.95 (m, 2H),0.78-0.03 (m, 19H); (ES, m/z): 1111 [M+H]⁺. [α]=−110.72°, T=27.2° C.,C=0.23 g/100 mL in MeOH.

Preparation Example 37 Synthesis of Compound 7-34A in Table 7, WhereinR^(a), R^(b), R′, R″, R′″ and R″″ are Each Methyl

Compound 7-34A was prepared in a similar way to compound 6-7A accordingto Schemes 10 to 12 shown below.

Experimental Details

Benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]propanoate:Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (7 g,15.57 mmol, 1.00 equiv),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.3 g, 15.71 mmol, 1.00 equiv), sodium carbonate (5 g, 47.17 mmol, 3.00equiv), dioxane (50 mL), water (10 mL), Pd(PPh₃)₄ (900 mg, 0.78 mmol,0.05 equiv). The resulting solution was stirred for 2 h at 75° C. Thesolids were filtered out. The filtrate was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 8 g (crude) of benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]propanoateas colorless oil. MS (ESI, m/z): 453 [M+H]⁺.

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid: Into a 1000-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-cyclopropylpropanoic acid (9 g,39.25 mmol, 1.00 equiv), tetrahydrofuran (500 mL), This was followed bythe addition of sodium hydride (4.7 g, 117.50 mmol, 3.00 equiv, 60%) inportions at 0° C. To this was added CH₃I (45 g, 317.04 mmol, 8.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirred for17 h at room temperature. The reaction was then quenched by the additionof water (500 mL). The resulting solution was extracted with 3×500 mL ofmethyl tert-butyl ether and the aqueous layers combined. The pH value ofthe solution was adjusted to 4 with Citric acid. The resulting solutionwas extracted with 3×500 mL of ethyl acetate and the organic layerscombined. The organic layer was washed with 1×500 mL of brine. Theorganic layer was dried over sodium sulfate and concentrated undervacuum. This resulted in 8.99 g (94%) of(2S)-2-[[(tert-butox-y)car-bonyl](m-ethy-l)amino]-3-cyclopropylpropanoicacid as yellow oil. MS (ESI, m/z): 242 [M−H]⁻.

Benzyl (2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate:Into a 250-mL 3-necked round-bottom flask, was placed benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]propanoate(8 g, 17.67 mmol, 1.00 equiv), tetrahydrofuran (60 mL), This wasfollowed by the additions of TBAF (6 g, 22.95 mmol, 1.20 equiv) inportions at 0° C. The resulting solution was stirred for 30 min at roomtemperature. The reaction was then quenched by the addition of water(200 mL). The resulting solution was extracted with 3×50 mL of ethylacetate and the organic layers combined. The organic layer was washedwith 3×50 mL of water and 1×50 mL of brine. The organic layer was driedover sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:7). This resulted in 3.5 g (59%) of benzyl(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate as awhite solid.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropyl-propanoate:Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid (4 g, 16.44 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (3g, 16.65 mmol, 1.00 equiv), tetrahydrofuran (30 mL), PPh₃ (5.2 g, 19.83mmol, 1.20 equiv). To this was added the DEAD (3.5 g, 20.10 mmol, 1.20equiv) in tetrahydrofuran (10 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 17 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:20). This resulted in 3 g (45%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate aswhite oil. MS (ESI, m/z): 406 [M+H]⁺.

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butox-y)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D6): Into a 50-mL 3-necked round-bottom flask, was placed benzyl(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate (1.3 g,3.84 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (1 g, 3.80 mmol, 1.00 equiv), dichloromethane (15 mL), This wasfollowed by the addition of DCC (872 mg, 4.23 mmol, 1.10 equiv),4-dimethylaminopyridine (516 mg, 4.22 mmol, 1.10 equiv) and HOBT (571mg, 4.23 mmol, 1.10 equiv) in portion at 0° C. The resulting solutionwas stirred for 17 h at room temperature. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:8). Thisresulted in 1.5 g (67%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)-ca-rbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas a white solid. MS (ESI, m/z): 584 [M+H]⁺.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-3-cyclopropyl-2-(methylamino)propanoate (DA10): Into a 100-mL3-necked round-bottom flask, was placed(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D10, 1.5 g, 3.70 mmol, 1.00 equiv), dichloromethane (30 mL), This wasfollowed by the addition of trifluoroacetic acid (7 mL) dropwise withstirring at 0° C. The resulting solution was stirred for 1 h at roomtemperature. The pH value of the solution was adjusted to 8 with sodiumbicarbonate (aq.). The resulting solution was extracted with 100 mL ofdichloromethane and the organic layers combined and dried over sodiumsulfate and concentrated under vacuum. This resulted in 1.4 g (crude) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-3-cyclopropyl-2-(methylamino)propanoate as a white solid. MS (ESI,m/z): 306 [M+H]⁺.

(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(ox-an-4-yl)phenyl]propanoicacid (DC6): Into a 250-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D6, 1.5 g, 2.57 mmol, 1.00 equiv), MeOH (80 mL) and Palladium carbon(800 mg). To the above mixture was introduced hydrogen. The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 1.3 g (crude) of(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-meth-ylpe-ntanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid as a white solid. MS (ESI, m/z): 496 [M+H]⁺.

(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](m-eth-yl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(TP7-34: Into a 100-mL 3-necked round-bottom flask, was placed DC6 (1.3g, 2.62 mmol, 1.00 equiv), DA10 (801 mg, 2.62 mmol, 1.00 equiv),dichloromethane (20 mL), The was followed by the addition of BOP-Cl (1.3g, 5.11 mmol, 2.00 equiv) in portions at 0° C. To this was added DIEA(678 mg, 5.25 mmol, 2.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred overnight at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted was applied onto a silica gel column with ethylacetate/petroleum ether (1:8). This resulted in 1.4 g (68%) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methy-l)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-me-thylpentanoateas a white solid. MS (ESI, m/z): 783 [M+H]⁺.

(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](m-eth-yl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (TA7-34): Into a 50-mL3-necked round-bottom flask, was placed TP7-34 (700 mg, 0.89 mmol, 1.00equiv), dichloromethane (15 mL). This was followed by the addition oftrifluoroacetic acid (3 mL), dropwise with stirring at 0° C. Theresulting solution was stirred for 1 h at room temperature. The pH valueof the solution was adjusted to 8 with sodium bicarbonate (aq.). Theresulting solution was extracted with 50 mL of dichloromethane and theorganic layers combined. The organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 650 mg(crude) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)car-bam-oyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (TA7-34) as a whitesolid. MS (ESI, m/z): 683 [M+H]⁺.

(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoy-l]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]propanoicacid (TC7-34): Into a 100-mL round-bottom flask, was placed TP7-34 (700mg, 0.89 mmol, 1.00 equiv), methanol (30 mL), Palladium carbon (100 mg).To the above mixture was introduced hydrogen. The resulting solution wasstirred for 40 min at room temperature. The solids were filtered out.The filtrate was concentrated under vacuum. This resulted in 600 mg(97%) of(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]propanoicacid as a white solid. MS (ESI, m/z): 693 [M+H]⁺.

Compound OP7-34: Into a 50-mL 3-necked round-bottom flask, was placedTA7-34 (650 mg, 0.95 mmol, 1.00 equiv), TC7-34 (600 mg, 0.87 mmol, 1.00equiv), dichloromethane (15 mL). This was followed by the addition ofBOP-Cl (486 mg, 2.00 equiv) in portions at 0° C. To this was added DIEA(246 mg, 1.90 mmol, 2.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred overnight at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:3). This resulted in 750 mg (58%) of OP7-34as a white solid. MS (ESI, m/z): 1358 [M+H]⁺.

(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyc-l-opropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethoxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (OA7-34): Into a 50-mL3-necked round-bottom flask, was placed OP7-34 (750 mg, 0.55 mmol, 1.00equiv), dichloromethane (8 mL), This was followed by the additions oftrifluoroacetic acid (2 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 1 h at room temperature. The pH valueof the solution was adjusted to 8 with sodium bicarbonate (aq.). Theresulting solution was extracted with 30 mL of dichloromethane and theorganic layers combined and dried in an oven under reduced pressure andconcentrated under vacuum. This resulted in 700 mg of(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxopropan-2-yl]oxy]-3-cyclopropyl-1-oxopro-pan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethoxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](meth-yl)c-arbamoyl]ethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phe-nyl]eth-yl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (OA7-34) as a whitesolid. MS (ESI, m/z): 1258 [M+H]⁺.

(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-4-fluor-o-4-methyl-2-(methylamino)pentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]pr-opanamido-]prop-anoyl]oxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phe-nyl]propanamido]propanoyl]oxy]propanoicacid (OAC7-34): Into a 50-mL round-bottom flask, was placed OA7-34 (700mg, 0.56 mmol, 1.00 equiv), methanol (30 mL), Palladium carbon (100 mg).To the above mixture was introduced hydrogen. The resulting solution wasstirred for 0.5 h at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. This resulted in 640 mg (98%) of(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phen-yl]propan-am-ido]propanoyl]oxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]propanoyl]oxy]propanoicacid (OAC7-30) as a white solid. MS (ESI, m/z): 1168 [M+H]⁺.

(3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(cyclopropylmethyl)-9,21-bis(2-fluoro-2-methylpropyl)-4,-10,12,16,22,24-hexamethyl-6,18-bis([[4-(oxan-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-te-traazacyclotetracosan-2,5,8,11,14,17,20,23-octone(7-34A): Into a 500-mL 3-necked round-bottom flask, was placed OAC7-34(640 mg, 0.55 mmol, 1.00 equiv), dichloromethane (200 mL). This wasfollowed by the addition of BOP-Cl (280 mg, 1.10 mmol, 2.00 equiv) inportions at 0° C. To this was added DIEA (141 mg, 1.09 mmol, 1.99 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered by filtration.The filtrate was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions (waters-2767):Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, Water and CH₃CN(70% CH₃CN up to 80% in 8 min); Detector, UV 254 nm. This resulted in85.8 mg (14%) of(3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(cyclopropylmethyl)-9,21-bis(2-fluoro-2-methylpropyl)-4,10,12,16,22,24-hexamethyl-6,18-bis([[4-(oxan-4-yl)phenyl]methyl])-1,7,-13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(7-34A) as a white solid. ¹H NMR (CD₃OD, 300 MHz) δ: 7.5-7.0 (m, 8H),5.96-4.9 (m, 8H), 4.19-3.94(m, 4H), 3.7-3.47 (m, 4H), 3.28-2.69 (m,18H), 2.39-1.2(m, 33H), 1.00-0.97 (m, 1H), 0.69-0.01 (m, 10H); MS (ESI,m/z): 1150 [M+H]⁺; [α]=−57.2°, T=27.2° C., C=1.0 g/100 mL in MeOH.

Preparation Example 38 Synthesis of Compound 7-30B in Table 7 WhereinR^(a) and R^(b) are Hydrogen, and R′, R″, R′″ and R″″ are Each Methyl

Compound 7-34B was prepared in a similar way to compound 6-7A accordingto Schemes 13 and 14 shown below.

Experimental Details

2-(benzyloxy)-2-oxoethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D9): Into a 100-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoicacid (1.5 g, 6.17 mmol, 1.00 equiv), benzyl 2-hydroxyacetate (1.02 g,6.14 mmol, 1.00 equiv) and dichloromethane (30 mL). This was followed bythe addition of DCC (1.52 g, 7.37 mmol, 1.20 equiv),4-dimethylaminopyridine (900 mg, 7.37 mmol, 1.20 equiv) and HOBt (1.0 g,7.40 mmol, 1.20 equiv) in portions at 0° C. The resulting solution wasstirred overnight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 2 g (83%) of 2-(benzyloxy)-2-oxoethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate asyellow oil. MS (ESI, m/z): 392 [M+H]⁺.

2-(benzyloxy)-2-oxoethyl (2S)-3-cyclopropyl-2-(methylamino)propanoate(DA9): Into a 50-mL round-bottom flask, was placed2-(benzyloxy)-2-oxoethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-cyclopropylpropanoate(D9, 1.8 g, 4.60 mmol, 1.00 equiv) and dichloromethane (16 mL). To thiswas added trifluoroacetic acid (3 mL) dropwise with stirring at 0° C.The resulting solution was stirred for 1 h at room temperature. The pHvalue of the solution was adjusted to 9 with sodium bicarbonate (aq.).The resulting solution was extracted with 2×20 mL of dichloromethane andthe organic layers combined. The organic layers were dried over sodiumsulfate and concentrated under vacuum. This resulted in 1.2 g (90%) of2-(benzyloxy)-2-oxoethyl (2S)-3-cyclopropyl-2-(methylamino) propanoateas light yellow oil. MS (ESI, m/z): 292 [M+H]⁺.

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D6): Into a 50-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (1 g, 3.80 mmol, 1.00 equiv), benzyl(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate (770mg, 2.28 mmol, 1.00 equiv) and dichloromethane (20 mL), This wasfollowed by the addition of DCC (730 mg, 3.54 mmol, 1.20 equiv),4-dimethylaminopyridine (430 mg, 3.52 mmol, 1.20 equiv) and HOBt (480mg, 3.55 mmol, 1.20 equiv). The resulting solution was stirred overnightat room temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:3). This resulted in 1.2 g(54%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas yellow oil. MS (ESI, m/z): 584 [M+H]⁺.

(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid (DC6): Into a 50-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(1.2 g, 2.06 mmol, 1.00 equiv), methanol (20 mL) and Palladium carbon(200 mg). To the above mixture was introduced hydrogen. The resultingsolution was stirred for 1.5 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 1.0 g (98%) of(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid as a white solid. MS (ESI, m/z): 496 [M+H]⁺.

(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(TP7-34B): Into a 50-mL round-bottom flask, was placed2-(benzyloxy)-2-oxoethyl (2S)-3-cyclopropyl-2-(methylamino)propanoate(1.0 g, 3.43 mmol, 1.00 equiv),(2R)-1-(benzyloxy)-3-[4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(580 mg, 0.99 mmol, 1.00 equiv), dichloromethane (20 mL), The wasfollowed by the addition of BOP-Cl (1.03 g, 4.05 mmol, 2.00 equiv) inportions at 0° C. To this was added DIEA (520 mg, 4.02 mmol, 2.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/hexane (1:3). This resulted in 1.1g (42%) of(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas yellow oil. MS (ESI, m/z): 769 [M+H]⁺.

(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (TA7-34B): Into a 50-mLround-bottom flask, was placed(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(TP7-34B, 560 mg, 0.73 mmol, 1.00 equiv) and dichloromethane (20 mL). Tothis was added trifluoroacetic acid (3 mL) dropwise with stirring at 0°C. The resulting solution was stirred for 1 h at room temperature. ThepH value of the solution was adjusted to 9 with sodium bicarbonate(aq.). The resulting solution was extracted with 2×20 mL ofdichloromethane and the organic layers combined. The organic layers weredried over sodium sulfate and concentrated under vacuum. This resultedin 0.50 g (crude) of(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate as brown oil. MS (ESI,m/z): 669 [M+H]⁺.

2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]aceticacid (TC7-34B): Into a 50-mL round-bottom flask, was placed(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(TP7-34B, 560 mg, 0.73 mmol, 1.00 equiv), methanol (20 mL) and Palladiumcarbon (50 mg). To the above mixture was introduced hydrogen. Theresulting solution was stirred for 1.5 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted in 0.50 g (crude) of2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]aceticacid as colorless oil. MS (ESI, m/z): 679 [M+H]⁺.

Compound OP7-34B: Into a 50-mL round-bottom flask, was placed(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (TA7-34B, 500 mg, 0.75mmol, 1.00 equiv),2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]aceticacid (TC7-34B, 500 mg, 0.74 mmol, 1.00 equiv), dichloromethane (20 mL),The was followed by the addition of BOP-Cl (420 mg, 1.65 mmol, 2.00equiv) in portions at 0° C. To this was added DIEA (210 mg, 1.62 mmol,2.00 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 0.6 g (60%) of OP7-34B as brown oil. MS (ESI, m/z): 1330[M+H]⁺.

(1R)-1-[[(2S)-1-([[(2S)-1-[(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethoxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]methoxy)-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (OA7-34B): Into a 50-mLround-bottom flask, was placed OP7-34B (600 mg, 0.45 mmol, 1.00 equiv)and dichloromethane (20 mL). To this was added trifluoroacetic acid (3mL) dropwise with stirring at 0° C. The resulting solution was stirredfor 1.5 h at room temperature. The pH value of the solution was adjustedto 9 with sodium bicarbonate (aq.). The resulting solution was extractedwith 2×10 mL of dichloromethane and the organic layers combined. Theorganic layers were dried over sodium sulfate and concentrated undervacuum. This resulted in 560 mg (crude) of(1R)-1-[[(2S)-1-([[(2S)-1-[(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethoxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]methoxy)-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate as yellow oil. MS (ESI,m/z): 1230 [M+H]⁺.

2-[[(2S)-2-[(2R)-2-[[(2S)-2-(2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]-N-methylacetamido)-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]aceticacid (OAC7-34B): Into a 50-mL round-bottom flask, was placed(1R)-1-[[(2S)-1-([[(2S)-1-[(1R)-1-[[(2S)-1-[2-(benzyloxy)-2-oxoethoxy]-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethoxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]methoxy)-3-cyclopropyl-1-oxopropan-2-yl](methyl)carbamoyl]-2-[4-(oxan-4-yl)phenyl]ethyl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (OA7-34B, 560 mg, 0.46mmol, 1.00 equiv), methanol (30 mL) and Palladium carbon (100 mg). Tothe above hydrogen was introduced. The resulting solution was stirredfor 1.5 h at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. This resulted in 200 mg (35%) of2-[[(2S)-2-[(2R)-2-[[(2S)-2-(2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]-N-methylacetamido)-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]-3-cyclopropylpropanoyl]oxy]aceticacid as light yellow oil. MS (ESI, m/z): 1140 [M+H]⁺.

(3S,6R,9S,15S,18R,21S)-3,15-bis(cyclopropylmethyl)-9,21-bis(2-fluoro-2-methylpropyl)-4,10,16,22-tetramethyl-6,18-bis([[4-(oxan-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(7-34B): Into a 250-mL round-bottom flask, was placed2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-2-(2-[[(2S)-3-cyclopropyl-2-[(2R)-2-[[(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]propanoyl]oxy]-N-methylacetamido)-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]propanoyl]oxy]aceticacid (OAC7-34B, 200 mg, 0.18 mmol, 1.00 equiv) and dichloromethane (70mL). This was followed by the addition of BOP-Cl (89 mg, 0.35 mmol, 2.00equiv) in portions at 0° C. To this was added DIEA (45 mg, 0.35 mmol,2.00 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (waters-2767): Column, SunFire Prep C18, 5um, 19*150 mm; mobile phase, Water and CH₃CN (70% CH₃CN up to 80% in 8min); Detector, UV 254 nm. This resulted in 64 mg (33%) of(3S,6R,9S,15S,18R,21S)-3,15-bis(cyclopropylmethyl)-9,21-bis(2-fluoro-2-methylpropyl)-4,10,16,22-tetramethyl-6,18-bis([[4-(oxan-4-yl)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octoneas a white solid. ¹H NMR (CD₃OD, 300 MHz) δ: 7.26-7.16 (m, 8H),5.65-5.35 (m, 5H), 4.90-4.72 (m, 5H), 4.06-4.02 (m, 4H), 3.61-3.52 (m,4H), 3.15-2.78 (m, 18H), 2.35-2.12 (m, 4H), 1.90-1.32 (m, 24H),0.65-0.08 (m, 10H); MS (ESI, m/z): 1150 [M+H]⁺; [α]=−90.83°, T=27.2° C.,C=0.48 g/100 mL in MeOH.

Preparation Example 39

Synthesis of Compound F4 wherein Cy¹ and Cy² are each

R¹ and R³ are each —CH₂CF(CH₃)₂; R² is —CH₂CH(CH₃)₂; R⁴ is C27; andR^(a), R^(b), R′, R″, R′″ and R″″ are each methyl.

Compound 7-30B was prepared according to the process in Schemes 15 and16 shown below.

Experimental Detail

(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]propanoicacid (DC16): Into a 100-mL round-bottom flask, was placed benzyl(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]propanoate(D16, 1 g, 2.65 mmol, 1.00 equiv), ethyl acetate (20 mL), Palladiumcarbon (400 mg). To the above mixture was introduced hydrogen. Theresulting solution was stirred for 2 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted in 750 mg (99%) of(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]propanoicacid as pink oil. MS (ES, m/z): 288 (M+H).

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (DA6): Into a 250-mLround-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D6, 2 g, 3.43 mmol, 1.00 equiv), DCM (10 mL), hydrogen chloride(dioxane, 20 mL). The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. The pHvalue of the solution was adjusted to 9 with aqueous sodium bicarbonate.The resulting solution was extracted with 2×30 mL of dichloromethane andthe organic layers combined and washed with 40 mL of brine. The organiclayer were collected and dried over sodium sulfate. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 1.6 g (97%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate as yellow oil. MS (ES,m/z): 484 (M+H).

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoate(TP-F4): Into a 100-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (DA6, 1.5 g, 3.10 mmol,1.00 equiv),(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]propanoicacid (DC16, 890 mg, 3.10 mmol, 1.00 equiv), dichloromethane (30 mL).This was followed by the addition of BOP-Cl (1.58 g, 6.21 mmol, 2.00equiv) at 0° C. in 10 min. To this was added DIEA (800 mg, 6.19 mmol,2.00 equiv) at 0° C. in 10 min. The resulting solution was stirred for 2h at room temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:2). This resulted in 1.4 g(60%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoateas yellow oil. MS (ES, m/z): 753 (M+H).

(2R)-2-[[(2S)-2-[(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid (TC-F4): Into a 100-mL round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[(2R)-2-[([4[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoate(TP-F4, 900 mg, 1.20 mmol, 1.00 equiv), ethyl acetate (20 mL), Palladiumcarbon (200 mg). To the above mixture was introduced hydrogen. Theresulting solution was stirred for 2 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted in 660 mg (83%) of(2R)-2-[[(2S)-2-[(2R)-2-[(1[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid as a white solid. MS (ES, m/z): 665 (M+H).

(R)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoyloxy)propanoicacid (DC2): Into a 100-mL round-bottom flask, was placed(S)—((R)-1-(benzyloxy)-1-oxopropan-2- yl)2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoate (D2, 1 g, 2.40mmol, 1.00 equiv), EA (30 mL), Palladium carbon (400 mg). To the aboveH₂ was introduced in. The resulting solution was stirred for 2 h at roomtemperature. The solids were filtered out. The filtrate was concentratedunder vacuum. This resulted in 720 mg (crude) of(R)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoyloxy)propanoicacid as yellow oil. MS (ES, m/z): 484 (M+H).

(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-3-[4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(TP-F4B): Into a 100-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate (DA6, 500 mg, 1.03mmol, 1.00 equiv),(R)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoyloxy)propanoicacid (DC2, 330 mg, 1.03 mmol, 1.00 equiv) in DCM (30 mL). This wasfollowed by the addition of BOP-Cl (528 mg, 2.06 mmol, 2.00 equiv) at 0°C. in 5 min. To this was added DIEA (267 mg, 2.06 mmol, 2.00 equiv) at0° C. in 5 min. The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:5). This resulted in 615 mg (76%) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-3-[4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate asyellow oil. MS (ES, m/z): 783 (M+H).

(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-3-[4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2S)-4-methyl-2-(methylamino)pentanoate (TA-F4): Into a 100-mLround-bottom flask, was placed(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-3-[4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(TP-F4B, 400 mg, 0.51 mmol, 1.00 equiv), hydrogen chloride (dioxane, 10mL). The resulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The pH value of thesolution was adjusted to 9 with aqueous sodium bicarbonate. Theresulting solution was extracted with 2×30 mL of dichloromethane and theorganic layers combined and washed with 30 mL of brine. The organicphase was collected and dried over sodium sulfate. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 400 mg (crude) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-3-[4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2S)-4-methyl-2-(methylamino)pentanoate as yellow oil. MS (ES, m/z): 683(M+H).

[(1R)-2-[[(1S)-1-[(1R)-2-[[(1S)-1-[(1R)-2-[[(1S)-1-[(1R)-2-benzyloxy-1-(3,6-dihydro-2H-pyran-4-ylmethyl)-2-oxo-ethoxy]carbonyl-3-fluoro-3-methyl-butyl]-methyl-amino]-1-methyl-2-oxo-ethoxy]carbonyl-3-methyl-butyl]-methyl-amino]-2-oxo-1-(tetrahydropyran-4-ylmethyl)ethoxy]carbonyl-3-fluoro-3-methyl-butyl]-methyl-amino]-1-methyl-2-oxo-ethyl]-[tert-butoxycarbonyl(methyl)amino]cyclopropanecarboxylate(OP-F4): Into a 100-mL round-bottom flask, was placed(2R)-2-[[(2S)-2-[(2R)-2-[([4[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid (TC-F4, 340 mg, 0.51 mmol, 1.00 equiv),(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-3-[4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2S)-4-methyl-2-(methylamino)pentanoate (TA-F4, 350 mg, 0.51 mmol, 1.00equiv), dichloromethane (15 mL). This was followed by the addition ofBOP-Cl (261 mg, 1.03 mmol, 2.00 equiv) at 0° C. in 5 min. To this wasadded DIEA (132 mg, 1.02 mmol, 2.00 equiv) at 0° C. in 5 min. Theresulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18 silica gel; mobile phase, H₂O and CH₃CN (50%CH₃CN up to 80% in 15 min and 80% CH₃CN up to 100% within 15 min);Detector, UV 220 nm. This resulted in 400 mg (59%) of OP-F4 as yellowoil. MS (ES, m/z): 1330 (M+H).

(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[1-[tert-butoxycarbonyl(methyl)amino]cyclopropanecarbonyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-(4-tetrahydropyran-4-ylphenyl)propanoyl]-methyl-amino]-4-methyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-(4-tetrahydropyran-4-ylphenyl)propanoicacid (OC-F4): Into a 100-mL round-bottom flask, was placed OP-F4 (400mg, 0.30 mmol, 1.00 equiv), ethyl acetate (15 mL), Palladium carbon (160mg). To the above mixture was introduced hydrogen. The resultingsolution was stirred for 2 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 350 mg (94%) of OC-F4 as yellow oil. MS (ES, m/z): 1242 (M+H).

(2R)-2-[(2S)-4-fluoro-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-4-fluoro-4-methyl-2-[methyl-[(2R)-2-[1-(methylamino)cyclopropanecarbonyl]oxypropanoyl]amino]pentanoyl]oxy-3-(4-tetrahydropyran-4-ylphenyl)propanoyl]-methyl-amino]-4-methyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-methyl-pentanoyl]oxy-3-(4-tetrahydropyran-4-ylphenyl)propanoicacid (OAC-F4): Into a 100-mL round-bottom flask, was placed OC-F4 (350mg, 0.28 mmol, 1.00 equiv), DCM (5 mL), hydrogen chloride (dioxane, 10mL). The resulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The pH value of thesolution was adjusted to 9 with aqueous sodium bicarbonate. Theresulting solution was extracted with 2×30 mL of dichloromethane and theorganic layers combined and washed with 40 mL of brine. The organiclayer was collected and dried over sodium sulfate. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 350 mg (crude) of OAC-F4 as yellow oil. MS (ES, m/z): 1142 (M+H).

(6R,9S,12R,15S,18R,21S,24R)-9,21-bis(2-fluoro-2-methylpropyl)-4,10,12,16,22,24-hexamethyl-15-(2-methylpropyl)-6,18-bis([[4-(oxan-4-yl)phenyl]methyl])-7,13,19,25-tetraoxa-4,10,16,22-tetraazaspiro[2.23]hexacosan-5,8,11,14,17,20,23,26-octone(F4): Into a 250-mL round-bottom flask, was placed OAC-F4 (300 mg, 0.26mmol, 1.00 equiv), dichloromethane (300 mL). This was followed by theaddition of BOP-Cl (134 mg, 0.53 mmol, 2.00 equiv) at 0° C. in 5 min. Tothis was added DIEA (102 mg, 0.79 mmol, 3.00 equiv) at 0° C. in 5 min.The resulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions (Waters I): Column,X Bridge Prep RP18, 5 um, 19×150 mm; mobile phase, water and CH₃CN (70%CH₃CN up to 90% acetonitrile in 7 min); Detector, UV 220 nm. Thisresulted in 116.5 mg (39%) of(6R,9S,12R,15S,18R,21S,24R)-9,21-bis(2-fluoro-2-methylpropyl)-4,10,12,16,22,24-hexamethyl-15-(2-methylpropyl)-6,18-bis([[4-(oxan-4-yl)phenyl]methyl])-7,13,19,25-tetraoxa-4,10,16,22-tetraazaspiro[2.23]hexacosan-5,8,11,14,17,20,23,26-octone(F4) as a white solid. MS (ES, m/z): 1098.0 (M+H); ¹H NMR (CD₃OD, 300MHz, ppm): δ 7.31-7.23 (m, 8H), 5.96-5.83 (m, 1H), 5.81-5.72 (m, 1H),5.71-5.60 (m, 1H), 5.59-5.31 (m, 2H), 5.31-5.09 (m, 2H), 4.18-3.95 (m,4H), 3.71-3.43 (m, 4H), 3.21-3.09 (m, 6H), 3.06-2.94 (m, 6H), 2.85-2.77(m, 6H), 2.26-2.18 (m, 4H), 2.05-1.61 (m, 11H), 1.49-1.26 (m, 18H),1.18-0.97 (m, 4H), 0.96-0.75 (m, 6H); [α]=−89.93°, T=24.7° C., C=0.29g/100 mL, MeOH.

Preparation Example 40 Synthesis of Compound 969-34A in Table 699wherein Each of R^(a), R^(b), R′, R″, R′″ and R″″ are Methyl

Compound 969-34A was prepared in a similar way to compound 6-7Aaccording to Scheme 17 shown below.

Experimental Details

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-4-fluoro-4-methyl-2-[(2R)—N-methyl-2-[[1-(methylamino)cyclopropyl]carbonyloxy]propanamido]pentanoate(TA-969-34): Into a 100-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoate(TP-F4) (300 mg, 0.40 mmol, 1.00 equiv), DCM (8 mL), hydrogen chloride(dioxane, 15 mL). The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. The pHvalue of the solution was adjusted to 9 with aqueous sodium bicarbonate.The resulting solution was extracted with 2×30 mL of dichloromethane andthe organic layers combined and washed with 30 mL of brine. The organiclayer was collected and dried over sodium sulfate. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 350 mg (crude) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-4-fluoro-4-methyl-2-[(2R)—N-methyl-2-[[1-(methylamino)cyclopropyl]carbonyloxy]propanamido]pentanoate as yellow oil. MS (ES, m/z): 653 (M+H).

[(1R)-2-[[(1S)-1-[(1R)-2-benzyloxy-1-(3,6-dihydro-2H-pyran-4-ylmethyl)-2-oxo-ethoxy]carbonyl-3-fluoro-3-methyl-butyl]-methyl-amino]-1-methyl-2-oxo-ethyl]1-[[(2R)-2-[(2S)-2-[[(2R)-2-[1-[tert-butoxycarbonyl(methyl)amino]cyclopropanecarbonyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-tetrahydropyran-4-yl-propanoyl]-methyl-amino]cyclopropanecarboxylate(OP-969-34): Into a 100-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-4-fluoro-4-methyl-2-[(2R)—N-methyl-2-[[1-(methylamino)cyclopropyl]carbonyloxy]propanamido]pentanoate(TA-969-34) (350 mg, 0.54 mmol, 1.00 equiv),(2R)-2-[[(2S)-2-[(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid (TC-F4) (330 mg, 0.50 mmol, 1.00 equiv), dichloromethane (20 mL).This was followed by the addition of BOP-Cl (274 mg, 1.08 mmol, 2.00equiv) at 0° C. in 5 min. To this was added DIEA (138 mg, 1.07 mmol,2.00 equiv) at 0° C. in 5 min. The resulting solution was stirred for 2h at room temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C18 silica gel; mobile phase, H₂O and CH₃CN (50% CH₃CN up to 100% in 20min); Detector, UV 220 nm. This resulted in 220 mg (34%) of OP-969-34 asyellow oil. MS (ES, m/z): 1230 (M+H).

(2R)-2-[[(2S)-2-[(2R)-2-([1-[(2R)-2-[[(2S)-2-[(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]cyclopropyl]carbonyloxy)-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid (OC-969-34): Into a 100-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[(2R)-2-([1-[(2R)-2-[[(2S)-2-[(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]cyclopropyl]carbonyloxy)-N-methylpropanamido]-4-fluoro-4-methylpentanoate(OP-969-34) (200 mg, 0.15 mmol, 1.00 equiv), ethyl acetate (10 mL),Palladium carbon (80 mg). To the above mixture was introduced hydrogen.The resulting solution was stirred for 2 h at room temperature. Thesolids were filtered out. The filtrate was concentrated under vacuum.This resulted in 200 mg (crude) of(2R)-2-[[(2S)-2-[(2R)-2-([1-[(2R)-2-[[(2S)-2-[(2R)-2-[(1-[[(tert-butoxy)carbonyl](methyl)amino]cyclopropyl)carbonyloxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-N-methyl-3-[4-(oxan-4-yl)phenyl]propanamido]cyclopropyl]carbonyloxy)-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(oxan-4-yl)phenyl]propanoicacid as yellow oil. MS (ES, m/z): 1212 (M+H).

(2R)-2-[(2S)-4-fluoro-2-[[(2R)-2-[1-[[(2R)-2-[(2S)-4-fluoro-4-methyl-2-[methyl-[(2R)-2-[1-(methylamino)cyclopropanecarbonyl]oxypropanoyl]amino]pentanoyl]oxy-3-(4-tetrahydropyran-4-ylphenyl)propanoyl]-methyl-amino]cyclopropanecarbonyl]oxypropanoyl]-methyl-amino]-4-methyl-pentanoyl]oxy-3-(4-tetrahydropyran-4-ylphenyl)propanoicacid (OAC-969-34): Into a 100-mL round-bottom flask, was placedOC-969-34 (200 mg, 0.17 mmol, 1.00 equiv), DCM (5 mL), hydrogen chloride(dioxane, 8 mL). The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. The pHvalue of the solution was adjusted to 9 with aqueous sodium bicarbonate.The resulting solution was extracted with 2×30 mL of dichloromethane andthe organic layers combined and washed with 40 mL of brine. The organiclayer was collected and dried over sodium sulfate. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 200 mg (crude) of OAC-969-34 as yellow oil. MS (ES, m/z): 1112 (M+H).

(6R,9S,12R,20R,23S,26R)-9,23-bis(2-fluoro-2-methylpropyl)-4,10,12,18,24,26-hexamethyl-6,20-bis([[4-(oxan-4-yl)phenyl]methyl])-7,13,21,27-tetraoxa-4,10,18,24-tetraazadispiro[2.11.2^[15].11^[3]]octacosan-5,8,11,14,19,22,25,28-octone(969-34A): Into a 250-mL round-bottom flask, was placed OAC969-34 (180mg, 0.16 mmol, 1.00 equiv), dichloromethane (50 mL). This was followedby the addition of BOP-Cl (83 mg, 0.33 mmol, 2.00 equiv) at 0° C. in 2min. To this was added DIEA (63 mg, 0.49 mmol, 3.00 equiv) at 0° C. in 2min. The resulting solution was stirred overnight at room temperature.The solids were filtered out. The filtrate was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions (Waters I): Column, X Bridge Prep RP18, 5 um, 19×150 mm;mobile phase, phase A: water and CH₃CN (60% CH₃CN up to 80% in 7 min);Detector, UV 220 nm. This resulted in 51.5 mg (29%) of(6R,9S,12R,20R,23S,26R)-9,23-bis(2-fluoro-2-methylpropyl)-4,10,12,18,24,26-hexamethyl-6,20-bis([[4-(oxan-4-yl)phenyl]methyl])-7,13,21,27-tetraoxa-4,10,18,24-tetraazadispiro[2.11.2^[15].11^[3]]octacosan-5,8,11,14,19,22,25,28-octone(969-34A) as a white solid. MS (ES, m/z): 1094 (M+H); ¹H NMR (CD₃OD, 300MHz, ppm): δ 7.22-7.20 (m, 8H), 5.93-4.93 (m, 6H), 4.07-4.03 (m, 4H),3.61-3.53 (m, 4H), 3.11-2.79 (m, 18H), 2.41-2.08 (m, 4H), 2.05-1.81 (m,1H), 1.81-1.76 (m, 9H), 1.76-1.24 (m, 20H), 1.08-1.06 (m, 3H), 0.85-0.72(m, 1H); [a]=−62.98°, T=27.4° C., C=0.10 g/100 mL in MeOH.

In addition to depsipeptide compounds of the invention described inExamples 33-40, the additional numbered compounds shown in Table 1038below (which are described above, wherein R′, R″, R′″ and R″″ are eachmethyl), were prepared in accordance with the synthetic proceduresdescribed in the examples with the exception that different dimercompounds having the desired functionality were selected to prepare thedesired depsipeptide compounds. The selected dimers are prepared in turnfrom the required monomer compounds. It will be apparent to the skilledperson that using this methodology additional depsipeptide compounds ofthe invention may be prepared using other monomer and dimer components.

TABLE 1038 Additional Compounds of Formula (I) Prepared Compound #Observed Mass 7-58B 1122 229-34A 1122 228-34A 1124 6-58B 1124 18-34A1094 4-34A 1118 30-34A 1188 32-34A 1218 5-34A 1150 35-34A 1220 31-34A1186 303-34A 1178 SAX965250* 1178 *Cy¹ and Cy² are p-THPphenyl (seeTable 7); R¹, R³ = —CH₂CF(CH₃)₂ and R², R⁴ are —CH₂CH₂cyclopropyl

Biological Activity Examples

Method A: Screening Method to Test Activity of Compounds AgainstHaemonchus contortus.

Twenty L1 Haemonchus contortus larvae were added to wells of amicrotitre plate containing a nutrient medium and the test compound inDMSO. An analysis was conducted at 4 days to determine the extent ofdevelopment of the larvae. Larvae exposed to DMSO alone served ascontrols. Compounds 228-34A and 969-34A exhibited median EC₅₀ valuesbetween 1.0 and 10 μM, compound 7-58A exhibited a median EC₅₀ valuebetween 0.1 μM and 1.0 μM, and compounds 4-34A, 5-34A, 7-34A, 18-34A,30-34A, 32-34A, 35-34A, 229-34A, and 303-34A exhibited median EC₅₀values of less than 0.1 μM when assessed at the 4 day time point. As acomparison, emodepside exhibits a median EC₅₀ value of between 1 μM and10 μM in this assay.

Compound 6-1A exhibited a median MIC₉₀ value between 1.0 and 10 μM,compounds 6-7A and 6-34A exhibited median MIC₉₀ values between 0.1 μMand 1.0 μM, and compounds 7-34A and 7-58A exhibited median MIC₉₀ valuesof less than 0.1 μM when assessed at the 4 day time point. As acomparison, emodepside exhibits a median EC₅₀ value of between 0.1 μMand 1 μM in this assay. The EC₅₀ and MIC₉₀ recordings were obtainedusing different instruments.

Method B: Screening Method to Test Activity of Compounds AgainstMicrofilaria of Dirofilaria immitis.

Microfilaria of Dirofilaria immitis were added to the wells of amicrotitre plate containing buffer and the test compounds in DMSO. Anassessment was conducted at 72 hours to determine survival of themicrofilaria. Microfilaria exposed to DMSO alone served as controls.Compounds 6-58A, 9-7A, 31-34A, and 969-34A exhibited median EC₅₀ valuesof between 1 μM and 10 μM, compounds 6-1A, 6-7A, and 6-34A exhibitedmedian EC₅₀ values of between 0.1 μM and 1.0 μM, and compounds 4-34A,5-34A, 7-34A, 7-58A, 18-34A, 30-34A, 32-34A, 228-34A, 229-34A, and303-34A exhibited median EC₅₀ values of less than 0.1 μM. As acomparison, emodepside exhibits a median EC₅₀ value of between 0.1 μMand 1 μM in this assay.

Method C: Screening Method to Evaluate the Efficacy of Compounds AgainstDirofilaria immitis In Vivo.

Beagle dogs were tested for microfilaria and heartworm antigen andreceived a full physical examination prior to inclusion in the study.Each dog was inoculated with 50 infective third-stage D. immitis larvaeon Day −30 using an isolate sensitive to macrocyclic lactones atstandard doses. Antigen testing performed on blood collected on Day 90confirmed that animals had not been exposed to D. immitis prior to theinduced infection.

In the study, five blocks of four or five dogs each were formed based ondescending Day −3 to Day 0 body weights. Within blocks, dogs wererandomly allocated to one of five treatment groups by lottery andtreated five times at monthly intervals with an oral solution of acompound of this invention according to table 1039 below. The controldogs were untreated. Treatment groups 2 and 3 included compounds outsidethe scope of this invention.

All animals were humanely euthanized on Day 159 and a necropsy wasperformed for parasite recovery and live D. immitis counts forindividual dogs. The percent efficacies by treatment group are listed inTable 1039.

TABLE 1039 Efficacy against D. immitis in beagles. Trt. # ofInvestigational Group Dogs Material Dose Dosing Days Efficacy 1 5 (—)control n/a n/a n/a 4 4 18-34A 0.1 mg/kg 0, 30, 60, 90, 100% & 120 5 418-34A 0.5 mg/kg 0, 30, 60, 90, 100% & 120

In this study, compound 18-34A from this invention (@ 0.1 and 0.5 mg/kg)administered orally (in solution) for five monthly doses, provided 100%efficacy against induced infections of a macrocyclic lactone susceptibleisolate of Dirofilaria immitis.

Having thus described in detail preferred embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

What is claimed is:
 1. An anthelmintic cyclic depsipeptide compound offormula (I), or a pharmaceutically or veterinarily acceptable saltthereof:

wherein: Cy¹ and Cy² are independently aryl, carbocyclic, heteroaryl orheterocyclic, each of which is optionally substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl and heteroaryl, wherein each cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl substituents of Cy¹ andCy² is optionally further independently substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂; R⁵ and R⁶ areindependently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthio,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,allcynyl, haloalkynyl, or the group —CH₂C(O)NHCH₂CF₃; or R⁵ and R⁶together with the atom(s) to which they are bonded form a C₃-C₆ cyclicgroup; R ′, R″, R′″ and R″″ are each independently hydrogen orC₁-C₃alkyl; R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl; and (a) R¹ is C₁-C₃ alkyl or C₁-C₃ haloalkyl,substituted by a 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R^(1′) is hydrogen or C₁-C₃alkyl; or R¹and R^(1′) together form a 2-6-membered carbon chain to form a ring; andR², R^(2′), R³, R^(3′), R⁴ and R^(4′) are each independently hydrogen orC₁-C₈ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsuifinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or (b) R² is C₁-C₃ alkyl orC₁-C₃ haloalkyl, substituted by a 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring; wherein said 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring may be further independently substituted by one or moresubstituents selected from the group consisting of alkyl, haloalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(2′) is hydrogen orC₁-C₃alkyl; or R² and R^(2′) together form a 2-6-membered carbon chainto form a ring; and R¹, R^(1′), R³, R^(3′), R⁴ and R^(4′) are eachindependently hydrogen or C₁-C₈ alkyl, optionally substituted by one ormore halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino; or (c) R³ is C₁-C₃ alkyl or C₁-C₃ haloalkyl, substitutedby a 3- to 8-membered non-aromatic carbocyclic or 3- to 8-memberedheterocyclic group; wherein said -3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsuLfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R^(3′) is hydrogen or C₁-C₃alkyl; or R³and R^(3′) together form a 2-6-membered carbon chain to form a ring; andR₁, R^(1′), R², R^(2′), R⁴ and R^(4′) are each independently hydrogen orC₁-C₈ alkyl, optionally substituted by one or more halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylarnino; or (d) R⁴ is C₁-C₃ alkyl orC₁-C₃ haloalkyl, substituted by a 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring; wherein said 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring may be further independently substituted by one or moresubstituents selected from the group consisting of alkyl, haloalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylarnino; and R^(4′) is hydrogen orC₁-C₃alkyl; or R⁴ and R^(4′) together form a 2-6-membered carbon chainto form a ring; and R¹, R², R^(2′), R³ and R ^(3′) are eachindependently hydrogen or C₁-C₈ alkyl, optionally substituted by one ormore halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino; or (e) R¹ and/or R² are each independently C₁-C₃ alkyl orC₁-C₃ haloalkyl substituted by a 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring; wherein said 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring(s) may be further independently substituted by one or moresubstituents selected from the group consisting of alkyl, haloalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(2′) areindependently hydrogen or C₁-C₃alkyl; or R¹ and R^(1′) together and/orR² and R^(2′) together independently form a 2-6-membered carbon chain toform a ring; and R³, R^(3′), R⁴ and R^(4′) are each independentlyhydrogen or C₁-C₈ alkyl, optionally substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino or dialkylamino; or (f) R¹and/or R³ are each independently C₁-C₃ alkyl or C₁-C₃ haloalkylsubstituted by a 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring(s) may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R^(1′) and/or R^(3′) are independentlyhydrogen or C₁-C₃alkyl; or R¹ and R^(1′) together and/or R³ and R^(3′)together independently form a 2-6-membered carbon chain to form a ring;and R², R^(2′), R⁴ and R^(4′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or (g) R¹ and/or R⁴ are eachindependently C₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring; wherein said 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylammo; and R^(1′) and/or R^(4′) areindependently hydrogen or C₁-C₃alkyl; or R¹ and R^(1′) together and/orR⁴ and R^(4′) together independently form a 2-6-membered carbon chain toform a ring; and R², R^(2′), R³ and R^(3′) are each independentlyhydrogen or C₁-C₈ alkyl, optionally substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino or dialkylamino; or (h) R²and/or R⁴ are each independently C₁-C₃ alkyl or C₁-C₃ haloalkylsubstituted by a 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring(s) may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfmyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino; and R^(2′) and/or R^(4′) are independently hydrogen orC₁-C₃alkyl; or R² and R^(2′) together and/or R⁴ and R^(4′) togetherindependently form a 2-6-membered carbon chain to form a ring; and R¹,R^(1′), R³ and R^(3′) are each independently hydrogen or C₁-C₈ alkyl,optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or (i) R² and/or R³ are eachindependently C₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring; wherein said 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfmyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(2′) and/or R^(3′) areindependently hydrogen or C₁-C₃alkyl; or R² and R^(2′) together and/orR³ and R^(3′) together independently form a 2-6-membered carbon chain toform a ring; and R¹, R^(1′), R⁴ and R^(4′) are each independentlyhydrogen or C₁-C₈ alkyl, optionally substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino or dialkylamino; or (j) R³and/or R⁴ are each independently C₁-C₃ alkyl or C₁-C₃ haloalkylsubstituted by a 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring(s) may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R³ and/or R^(4′) are independently hydrogenor C₁-C₃alkyl; or R³ and R^(3′) together and/or R⁴ and R^(4′) togetherindependently form a 2-6-membered carbon chain to form a ring; and R¹,R^(1′), R² and R^(2′) are each independently hydrogen or C₁-C₈ alkyl,optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or (k) R¹ and/or R² and/or R³are each independently C₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a3- to 8-membered non-aromatic carbocyclic or 3- to 8-memberedheterocyclic ring; wherein said 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring(s) may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R^(1′) and/or R^(2′) and/or R^(3′) areindependently hydrogen or C₁-C₃alkyl; or R¹ and R^(1′) together and/orR² and R^(2′) together and/or R³ and R^(3′) together independently forma 2-6-membered carbon chain to form a ring; and R⁴ and R^(4′) areindependently hydrogen or C₁-C₈ alkyl, optionally substituted by one ormore halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfmyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino; or (l) R² and/or R³ and/or R⁴ are each independently C₁-C₃alkyl or C₁-C₃ haloalkyl substituted by a 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring; wherein said 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring(s) may be further independently substituted by one or moresubstituents selected from the group consisting of alkyl, haloalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(2′) and/or R^(3′)and/or R^(4′) are independently hydrogen or C₁-C₃alkyl; or R² and R^(2′)together and/or R³ and R^(3′) together and/or R⁴ and R^(4′) togetherindependently form a 2-6-membered carbon chain to form a ring; and R¹and R^(1′) are independently hydrogen or C₁-C₈ alkyl, optionallysubstituted by one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino; or (m) R¹ and/or R³ and/or R⁴ are eachindependently C₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring; wherein said 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(3′)and/or R^(4′) are independently hydrogen or C₁-C₃alkyl; or R¹ and R^(1′)together and/or R³ and R^(3′) together and/or R⁴ and R^(4′) togetherindependently form a 2-6-membered carbon chain to form a ring; and R²and R^(2′) are independently hydrogen or C₁-C₈ alkyl, optionallysubstituted by one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino; or (n) R¹ and/or R² and/or R⁴ are eachindependently C₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring; wherein said 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(2′)and/or R^(4′) are independently hydrogen or C₁-C₃alkyl; or R¹ and R^(1′)together and/or R² and R^(2′) together and/or R⁴ and R^(4′) togetherindependently form a 2-6-membered carbon chain to form a ring; and R³and R^(3′) are independently hydrogen or C₁-C₈ alkyl, optionallysubstituted by one or more halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino or dialkylamino; or (o) R¹ and/or R² and/or R³ and/or R⁴ areeach independently C₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring; wherein said 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(2′)and/or R^(3′) and/or R^(4′) are independently hydrogen or C₁-C₃alkyl; orR¹ and R^(1′) together and/or R² and R^(2′) together and/or R³ andR^(3′) together and/or R⁴ and R^(4′) together independently form a2-6-membered carbon chain to form a ring.
 2. The anthelmintic cyclicdepsipeptide of claim 1, wherein (e) R¹ and/or R² are each independentlyC₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a 3- to 8-memberednon-aromatic carbocyclic or 3- to 8-membered heterocyclic ring; whereinsaid 3- to 8-membered non-aromatic carbocyclic or 3- to 8-memberedheterocyclic ring(s) may be further independently substituted by one ormore substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(1′) and/or R^(2′) areindependently hydrogen or C₁-C₃alkyl; or R¹ and R^(1′) together and/orR² and R^(2′) together independently form a 2-6-membered carbon chain toform a ring; and R³, R^(3′), R⁴ and R^(4′) are each independentlyhydrogen or C₁-C₈ alkyl, optionally substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino or dialkylamino; or (f) R¹and/or R³ are each independently C₁-C₃ alkyl or C₁-C₃ haloalkylsubstituted by a 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring(s) may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R^(1′) and/or R^(3′) are independentlyhydrogen or C₁-C₃alkyl; or R¹ and R^(1′) together and/or R³ and R^(3′)together independently form a 2-6-membered carbon chain to form a ring;and R², R^(2′), R⁴ and R^(4′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or (g) R¹ and/or R⁴ are eachindependently C₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring; wherein said 3-to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyallcoxy, oxo,cyano, amino, alkylamino and dialkcylamino; and R^(1′) and/or R^(4′) areindependently hydrogen or C₁-C₃alkyl; or R¹ and R^(1′) together and/orR⁴ and R^(4′) together independently form a 2-6-membered carbon chain toform a ring; and R², R^(2′), R³ and R^(3′) are each independentlyhydrogen or C₁-C₈ alkyl, optionally substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino or dialkylamino; or (h) R²and/or R⁴ are each independently C₁-C₃ alkyl or C₁-C₃ haloalkylsubstituted by a 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3- to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring(s) may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R^(2′) and/or R^(4′) are independentlyhydrogen or C₁-C₃alkyl; or R² and R^(2′) together and/or R⁴ and R^(4′)together independently form a 2-6-membered carbon chain to form a ring;and R¹, R^(1′), R³ and R^(3′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino; or (i) R² and/or R³ are eachindependently C₁-C₃ alkyl or C₁-C₃ haloalkyl substituted by a 3- to8-membered non-aromatic carbocyclic or 3- to 8-membered heterocyclicring; wherein said 3-to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring(s) may be further independently substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R^(2′) and/or R^(3′) areindependently hydrogen or C₁-C₃alkyl; or R² and R^(2′) together and/orR³ and R^(3′) together independently form a 2-6-membered carbon chain toform a ring; and R¹, R^(1′), R⁴ and R^(4′) are each independentlyhydrogen or C₁-C₈ alkyl, optionally substituted by one or more halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino or dialkylamino; or (j) R³and/or R⁴ are each independently C₁-C₃ alkyl or C₁-C₃ haloalkyl,substituted by a 3- to 8-membered non-aromatic carbocyclic or 3- to8-membered heterocyclic ring; wherein said 3-to 8-membered non-aromaticcarbocyclic or 3- to 8-membered heterocyclic ring(s) may be furtherindependently substituted by one or more substituents selected from thegroup consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R^(3′) and/or R^(4′) are independentlyhydrogen or C₁-C₃alkyl; or R³ and R^(3′) together and/or R⁴ and R^(4′)together independently form a 2-6-membered carbon chain to form a ring;and R¹, R^(1′), R² and R^(2′) are each independently hydrogen or C₁-C₈alkyl, optionally substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino or dialkylamino.
 3. The anthelmintic cyclicdepsipeptide of claim 1, wherein one, two, three or four of R¹ to R⁴ ismethylene or methylene substituted by one or two halogen atoms, whichare further substituted by a 3- to 8-membered non-aromatic carbocyclicor 3- to 8-membered heterocyclic ring, wherein said 3- to 8-memberednon-aromatic carbocyclic or 3- to 8-membered heterocyclic rings areindependently optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and theothers of R¹ to R⁴ are independently C₁-C₆ alkyl optionallyindependently substituted by one or more halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, halothio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.
 4. The anthelmintic cyclicdepsipeptide of claim 2, wherein R¹ and R³ are independently selectedfrom C₂-C₆ alkyl, optionally independently substituted by one or morehalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulforiyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino ordialkylamino.
 5. The anthelmintic cyclic depsipeptide of claim 4,wherein R¹ and R³ are independently selected from C₂-C₆ alkyl,optionally independently substituted by one or more halogen.
 6. Theanthelmintic cyclic depsipeptide of claim 4, wherein R¹ and R³ are bothindependently selected from C₃-C₅ alkyl independently substituted by oneor more fluoro.
 7. The anthelmintic cyclic depsipeptide of claim 3,wherein one, two, three or four of R¹ to R⁴ are one of C1 to C6 or C9 toC20:


8. The anthelmintic cyclic depsipeptide of claim 7, wherein one, two,three or all four of R¹ to R⁴ are each independently one of C1 to C6 orC9 to C20; and the others of R¹ to R⁴ are independently C₂-C₆ alkyl,optionally substituted by one or more halogen.
 9. The anthelminticcyclic depsipeptide of claim 7, wherein R¹ and R³ are each independentlyone of C1 to C6 or C9 to C20; and R² and R⁴ are independently2,2-dimethylpropyl or 2-methylpropyl, substituted by one or morehalogen.
 10. The anthelmintic cyclic depsipeptide of claim 7, wherein R²and R⁴ are each independently one of C1 to C6 or C9 to C20; and R¹ andR³ are independently 2,2-dimethylpropyl or 2-methylpropyl, substitutedby one or more halogen.
 11. The anthelmintic cyclic depsipeptide ofclaim 10, wherein R² and R⁴ are each independently C1, C9, C10, or C16;and R¹ and R³ are independently 2,2-dimethylpropyl or 2-methylpropyl,substituted by one or more fluorine.
 12. The anthelmintic cyclicdepsipeptide of claim 9, wherein R¹ and R³ are each independently C1,C9, C10, or C16; and R² and R⁴ are independently 2,2-dimethylpropyl or2-methylpropyl, substituted by one or more fluorine.
 13. Theanthelmintic cyclic depsipeptide of claim 12, wherein R¹ and R³ are C1;and R² and R⁴ are independently 2,2-dimethylpropyl or 2-methylpropylsubstituted by one or more fluorine.
 14. The anthelmintic cyclicdepsipeptide of claim 6, wherein R² and R⁴ are each C₁-C₃alkylsubstituted by cyclopropyl; and R¹ and R³ are independently2,2-dimethylpropyl or 2-methylpropyl substituted by one or morefluorine.
 15. The anthelmintic cyclic depsipeptide of claim 1, whereinCy¹ and Cy² are independently phenyl, a 5-membered heteroaryl or a6-membered heteroaryl, each optionally independently substituted withone or more halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio,halothio, thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R₅R₆NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heterocyclyl, aryl orheteroaryl, wherein each cycloalkyl, heterocyclyl, aryl or heteroarylsubstituent is optionally further substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, halothio, thioamido,amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R₅R₆NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—,—CN and —NO₂.
 16. Theanthelmintic cyclic depsipeptide of claim 15, wherein Cy¹ and Cy² areindependently phenyl, optionally independently substituted with halogen,—CN, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, halothio, R⁵R⁶NC(O)— or heterocyclyl, wherein eachcycloalkyl and heterocyclyl is optionally substituted with halogen. 17.The anthelmintic cyclic depsipeptide of claim 15, wherein Cy¹ and Cy²are independently phenyl, optionally substituted with t-butyl, —CF₃,—OCF₃, —SCF₃, morpholinyl, piperidinyl, tetrahydropyranyl, cyclopentyl,cyclohexyl, fluoro or —SF₅, wherein said morpholinyl, piperidinyl,tetrahydropyranyl, cyclopentyl and cyclohexyl is optionally substitutedwith one or more halogen atoms.
 18. The anthelmintic cyclic depsipeptideof claim 17, wherein Cy¹ and Cy² are the same and are each


19. The anthelmintic cyclic depsipeptide of claim 17, wherein Cy¹ andCy² are the same and are each:


20. The anthelmintic cyclic depsipeptide of claim 17, wherein Cy¹ andCy² are the same and are each para-t-butylphenyl.
 21. The anthelminticcyclic depsipeptide of claim 4, wherein: R¹ and R³ are bothindependently selected from C₃-C₅ alkyl substituted with one or morefluoro; R² and R⁴ are each independently C₁-C₃alkyl substituted bycyclopropyl; R^(1′), R^(2′), R^(3′) and R^(4′) are H; Cy¹ and Cy² areeach independently phenyl substituted with halogen, C₁-C₆ alkyl,C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, —OCF₃, —SCF₃, SF₅ or heterocyclyl,wherein said C₃-C₆ cycloalkyl or heterocyclyl may be substituted withone or more halogen atoms; R′, R″, R′″ and R″″ are each independentlyC₁-C₃alkyl; and R^(a) and R^(b) are independently C₁-C₃alkyl.
 22. Theanthelmintic cyclic depsipeptide of claim 4, wherein: R¹ and R³ are—CH₂—C(CH₃)₃ or —CH₂—CF(CH₃)₂; R² and R⁴ are each C₁-C₃alkyl substitutedby cyclopropyl; R^(1′), R^(2′), R^(3′) and R^(4′) are H; R′, R″, R′″ andR″″ are CH₃; Cy¹ and Cy² are each independently phenyl substituted withhalogen, t-butyl, CF₃, C₃-C₆ cycloalkyl, —OCF₃, —SCF₃, SF₅, morpholinyl,tetrahydropyranyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein said morpholinyl, tetrahydropyranyl, piperidinyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl may be substitutedwith one or more halogen atoms; and R^(a) and R^(b) are independentlyCH₃.
 23. An anthelmintic pharmaceutical or veterinary compositioncomprising the anthelmintic cyclic depsipeptide of claim 1, or apharmaceutically or veterinarily acceptable salt thereof, in combinationwith a pharmaceutically or veterinarily acceptable carrier.
 24. Ananthelmintic pharmaceutical or veterinary composition comprising theanthelmintic cyclic depsipeptide of claim 1, or a pharmaceutically orveterinarily acceptable salt thereof, in combination with one or moreadditional parasiticidal active agent(s) and a pharmaceutically orveterinarily acceptable carrier.
 25. The anthelmintic cyclicdepsipeptide of claim 22, wherein: R² and R⁴ are each methylene orethylene substituted by cyclopropyl; and Cy¹ and Cy² are eachindependently phenyl substituted by morpholinyl, tetrahydropyranyl,t-butyl, —OCF₃ or CF₃.
 26. The anthelminitic cyclic depsipeptide ofclaim 25, wherein: R¹ and R³ are —CH₂—CF(CH₃)₂; and Cy¹ and Cy² are eachindependently phenyl substituted by tetrahydropyranyl, t-butyl, —OCF₃ orCF₃.